# gene_set_details

systematic_name: M16161
exact_source: Table 4AS: Favorable
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top genes associated with favorable survival after surgery of patients with epithelioid mesothelioma.

description_full:
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systematic_name: M10263
exact_source: Table 4AS: Unfavorable
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top genes associated with unfavorable survival after surgery of patients with epithelioid mesothelioma.

description_full:
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systematic_name: M4967
exact_source: Table 4S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression pattern in adult male germ cell tumors (GCT) correlates with POU5F1 [GeneID=5460].

description_full:
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systematic_name: M7995
exact_source: Table 3S: Subtype=S2
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes from 'subtype S2' signature of hepatocellular carcinoma (HCC): proliferation, MYC and AKT1 [GeneID=4609;207] activation.

description_full:
  Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomic-based classification for HCC have yielded highly divergent results, indicating difficulty in identifying unified molecular anatomy. We performed a meta-analysis of gene expression profiles in data sets from eight independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed three robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum alpha-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of beta-catenin mutation but rather was the result of transforming growth factor-beta activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene expression profiles and highlight the power of integrating multiple data sets to define a robust molecular taxonomy of the disease. [Cancer Res 2009;69(18):7385-92].


description_brief: Genes up-regulated in hepatoblastoma samples compared to normal liver tissue.
systematic_name: M14601
exact_source: Table 3S: Fold change HB/NL >= 2
source_species_code: HS
GEO_id: E-MEXP-1852,E-MEXP-1853,E-MEXP-1851
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Hepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/beta-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. beta-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.


systematic_name: M2650
exact_source: Table 10S
source_species_code: HS
GEO_id: E-MEXP-1852,E-MEXP-1853,E-MEXP-1851
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes whose expression classifies hepatoblastoma tumors as belonging to either rC1 or rC2 subtypes and whose expression predicts poor survival.

description_full:
  Hepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/beta-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. beta-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.


systematic_name: M885
exact_source: Table 1: d-Value > 0
source_species_code: HS
GEO_id: GSE6691
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes exclusively up-regulated in B lymphocytes from CLL (chronic lymphocytic leukemia) patients but with a similiar expression pattern in the normal cells and in the cells from WM (Waldenstroem's macroblobulinemia) patients.

description_full:
  The tumoral clone of Waldenström's macroglobulinemia (WM) shows a wide morphological heterogeneity, which ranges from B lymphocytes (BL) to plasma cells (PC). By means of genome-wide expression profiling we have been able to identify genes exclusively deregulated in BL and PC from WM, but with a similar expression pattern in their corresponding cell counterparts from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), as well as normal individuals. The differentially expressed genes have important functions in B-cell differentiation and oncogenesis. Thus, two of the genes downregulated in WM-BL were IL4R, which plays a relevant role in CLL B-cell survival, and BACH2, which participates in the development of class-switched PC. Interestingly, one of the upregulated genes in WM-BL was IL6. A set of four genes was able to discriminate clonal BL from WM and CLL: LEF1 (WNT/beta-catenin pathway), MARCKS, ATXN1 and FMOD. We also found deregulation of genes involved in plasma cell differentiation such as PAX5, which was overexpressed in WM-PC, and IRF4 and BLIMP1, which were underexpressed. In addition, three of the target genes activated by PAX5 - CD79, BLNK and SYK - were upregulated in WM-PC. In summary, these results indicate that both PC and BL from WM are genetically different from the MM and CLL cell counterpart.


systematic_name: M19492
exact_source: Table 1: d-Value < 0
source_species_code: HS
GEO_id: GSE6691
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes exclusively down-regulated in B lymphocytes from CLL (chronic lymphocytic leukemia) patients but with a similiar expression pattern in the normal cells and in the cells from WM (Waldenstroem's macroblobulinemia) patients.

description_full:
  The tumoral clone of Waldenström's macroglobulinemia (WM) shows a wide morphological heterogeneity, which ranges from B lymphocytes (BL) to plasma cells (PC). By means of genome-wide expression profiling we have been able to identify genes exclusively deregulated in BL and PC from WM, but with a similar expression pattern in their corresponding cell counterparts from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), as well as normal individuals. The differentially expressed genes have important functions in B-cell differentiation and oncogenesis. Thus, two of the genes downregulated in WM-BL were IL4R, which plays a relevant role in CLL B-cell survival, and BACH2, which participates in the development of class-switched PC. Interestingly, one of the upregulated genes in WM-BL was IL6. A set of four genes was able to discriminate clonal BL from WM and CLL: LEF1 (WNT/beta-catenin pathway), MARCKS, ATXN1 and FMOD. We also found deregulation of genes involved in plasma cell differentiation such as PAX5, which was overexpressed in WM-PC, and IRF4 and BLIMP1, which were underexpressed. In addition, three of the target genes activated by PAX5 - CD79, BLNK and SYK - were upregulated in WM-PC. In summary, these results indicate that both PC and BL from WM are genetically different from the MM and CLL cell counterpart.


systematic_name: M13976
exact_source: Table 2: d-Value > 0
source_species_code: HS
GEO_id: GSE6691
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes exclusively up-regulated in B lymphocytes from WM (Waldenstroem's macroblobulinemia) patients but with a similiar expression pattern in the normal cells and in the cells from CLL (chronic lymphocytic leukemia) patients.

description_full:
  The tumoral clone of Waldenström's macroglobulinemia (WM) shows a wide morphological heterogeneity, which ranges from B lymphocytes (BL) to plasma cells (PC). By means of genome-wide expression profiling we have been able to identify genes exclusively deregulated in BL and PC from WM, but with a similar expression pattern in their corresponding cell counterparts from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), as well as normal individuals. The differentially expressed genes have important functions in B-cell differentiation and oncogenesis. Thus, two of the genes downregulated in WM-BL were IL4R, which plays a relevant role in CLL B-cell survival, and BACH2, which participates in the development of class-switched PC. Interestingly, one of the upregulated genes in WM-BL was IL6. A set of four genes was able to discriminate clonal BL from WM and CLL: LEF1 (WNT/beta-catenin pathway), MARCKS, ATXN1 and FMOD. We also found deregulation of genes involved in plasma cell differentiation such as PAX5, which was overexpressed in WM-PC, and IRF4 and BLIMP1, which were underexpressed. In addition, three of the target genes activated by PAX5 - CD79, BLNK and SYK - were upregulated in WM-PC. In summary, these results indicate that both PC and BL from WM are genetically different from the MM and CLL cell counterpart.


systematic_name: M11733
exact_source: Table 2: d-Value < 0
source_species_code: HS
GEO_id: GSE6691
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes exclusively down-regulated in B lymphocytes from WM (Waldenstroem's macroblobulinemia) patients but with a similiar expression pattern in the normal cells and in the cells from CLL (chronic lymphocytic leukemia) patients.

description_full:
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systematic_name: M19443
exact_source: Table 3: d-Value < 0
source_species_code: HS
GEO_id: GSE6691
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes exclusively up-regulated in plasma cells from MM (multiple myeloma) patients but with a similiar expression pattern in the normal cells and in the cells from WM (Waldenstroem's macroblobulinemia) patients.

description_full:
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systematic_name: M17096
exact_source: Table 4
source_species_code: HS
GEO_id: GSE6691
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes exclusively up-regulated in B lymphocytes from WM (Waldenstroem's macroglobulinemia) but with a similar expression profile in MM (macroglobulinemia) and normal cells.

description_full:
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systematic_name: M1992
exact_source: Table 7S: Normal Old > 0 & WS > 0 & |Normal Old - WS| < 0.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated similarly  in primary fibroblast cultures from Werner syndrom patients and normal old donors compared to those from normal young donors.

description_full:
  Werner syndrome (WS) is a premature aging disorder, displaying defects in DNA replication, recombination, repair, and transcription. It has been hypothesized that several WS phenotypes are secondary consequences of aberrant gene expression and that a transcription defect may be crucial to the development of the syndrome. We used cDNA microarrays to characterize the expression of 6,912 genes and ESTs across a panel of 15 primary human fibroblast cell lines derived from young donors, old donors, and WS patients. Of the analyzed genes, 6.3% displayed significant differences in expression when either WS or old donor cells were compared with young donor cells. This result demonstrates that the WS transcription defect is specific to certain genes. Transcription alterations in WS were strikingly similar to those in normal aging: 91% of annotated genes displayed similar expression changes in WS and in normal aging, 3% were unique to WS, and 6% were unique to normal aging. We propose that a defect in the transcription of the genes as identified in this study could produce many of the complex clinical features of WS. The remarkable similarity between WS and normal aging suggests that WS causes the acceleration of a normal aging mechanism. This finding supports the use of WS as an aging model and implies that the transcription alterations common to WS and normal aging represent general events in the aging process.


systematic_name: M1993
exact_source: Table 7S: Normal old < 0 & WS < 0 & |Normal Old - WS| < 0.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated similarly  in primary fibroblast cultures from Werner syndrom patients and normal old donors compared to those from normal young donors.

description_full:
  Werner syndrome (WS) is a premature aging disorder, displaying defects in DNA replication, recombination, repair, and transcription. It has been hypothesized that several WS phenotypes are secondary consequences of aberrant gene expression and that a transcription defect may be crucial to the development of the syndrome. We used cDNA microarrays to characterize the expression of 6,912 genes and ESTs across a panel of 15 primary human fibroblast cell lines derived from young donors, old donors, and WS patients. Of the analyzed genes, 6.3% displayed significant differences in expression when either WS or old donor cells were compared with young donor cells. This result demonstrates that the WS transcription defect is specific to certain genes. Transcription alterations in WS were strikingly similar to those in normal aging: 91% of annotated genes displayed similar expression changes in WS and in normal aging, 3% were unique to WS, and 6% were unique to normal aging. We propose that a defect in the transcription of the genes as identified in this study could produce many of the complex clinical features of WS. The remarkable similarity between WS and normal aging suggests that WS causes the acceleration of a normal aging mechanism. This finding supports the use of WS as an aging model and implies that the transcription alterations common to WS and normal aging represent general events in the aging process.


systematic_name: M1994
exact_source: Table 7S: Normal Old > 0 & |Normal Old - WS| >= 0.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinctly up-regulated in primary fibroblast cultures from normal old donors compared to those from normal young donors.

description_full:
  Werner syndrome (WS) is a premature aging disorder, displaying defects in DNA replication, recombination, repair, and transcription. It has been hypothesized that several WS phenotypes are secondary consequences of aberrant gene expression and that a transcription defect may be crucial to the development of the syndrome. We used cDNA microarrays to characterize the expression of 6,912 genes and ESTs across a panel of 15 primary human fibroblast cell lines derived from young donors, old donors, and WS patients. Of the analyzed genes, 6.3% displayed significant differences in expression when either WS or old donor cells were compared with young donor cells. This result demonstrates that the WS transcription defect is specific to certain genes. Transcription alterations in WS were strikingly similar to those in normal aging: 91% of annotated genes displayed similar expression changes in WS and in normal aging, 3% were unique to WS, and 6% were unique to normal aging. We propose that a defect in the transcription of the genes as identified in this study could produce many of the complex clinical features of WS. The remarkable similarity between WS and normal aging suggests that WS causes the acceleration of a normal aging mechanism. This finding supports the use of WS as an aging model and implies that the transcription alterations common to WS and normal aging represent general events in the aging process.


systematic_name: M1995
exact_source: Table 7S: Normal Old < 0 & |Normal Old -WS| >= 0.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinctly down-regulated in primary fibroblast cultures from normal old donors compared to those from normal young donors.

description_full:
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systematic_name: M1996
exact_source: Table 7S: WS > 0 & |Normal Old - WS| >= 0.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinctly up-regulated in primary fibroblast cultures from Werner syndrom patients compared to those from normal young donors.

description_full:
[cell repeats an earlier one in this file: 1426 characters]


systematic_name: M1997
exact_source: Table 7S: WS > 0 & |Normal Old - WS| >= 0.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinctly down-regulated in primary fibroblast cultures from Werner syndrom patients compared to those from normal young donors.

description_full:
[cell repeats an earlier one in this file: 1426 characters]


systematic_name: M10778
exact_source: Fig. 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in T cell acute lymphocytic leukemia (T-ALL) patients refractory to chemotherapy treatment.

description_full:
  Gene expression profiles were examined in 33 adult patients with T-cell acute lymphocytic leukemia (T-ALL). Nonspecific filtering criteria identified 313 genes differentially expressed in the leukemic cells. Hierarchical clustering of samples identified 2 groups that reflected the degree of T-cell differentiation but was not associated with clinical outcome. Comparison between refractory patients and those who responded to induction chemotherapy identified a single gene, interleukin 8 (IL-8), that was highly expressed in refractory T-ALL cells and a set of 30 genes that was highly expressed in leukemic cells from patients who achieved complete remission. We next identified 19 genes that were differentially expressed in T-ALL cells from patients who either had a relapse or remained in continuous complete remission. A model based on the expression of 3 of these genes was predictive of duration of remission. The 3-gene model was validated on a further set of T-ALL samples from 18 additional patients treated on the same clinical protocol. This study demonstrates that gene expression profiling can identify a limited number of genes that are predictive of response to induction therapy and remission duration in adult patients with T-ALL.


systematic_name: M16530
exact_source: Table 3S: Subgroup = CD-1
source_species_code: HS
GEO_id: GSE2658
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Top 50 down-regulated genes in cluster CD-1 of multiple myeloma samples with the characteristic expression spike of CCND1 [GeneID=595].

description_full:
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systematic_name: M17523
exact_source: Table 3S: Subgroup = CD-2
source_species_code: HS
GEO_id: GSE2658
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Top 50 down-regulated genes in cluster CD-2 of multiple myeloma samples with the charachteristic expression spike of CCND3 [GeneID=896].

description_full:
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systematic_name: M4697
exact_source: Table 3S: Subgroup = HP
source_species_code: HS
GEO_id: GSE2658
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top 50 down-regulated genes in cluster HP of multiple myeloma samples characterized by a hyperploid signature.

description_full:
[cell repeats an earlier one in this file: 1481 characters]


systematic_name: M513
exact_source: Table 3S: Subgroup = MF
source_species_code: HS
GEO_id: GSE2658
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top 50 down-regulated genes in cluster MF of multiple myeloma samples with characteristic expression spike of MAF family transcription factors.

description_full:
[cell repeats an earlier one in this file: 1481 characters]


systematic_name: M18567
exact_source: Table 3S: Subgroup = MS
source_species_code: HS
GEO_id: GSE2658
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Top 50 down-regulated genes in cluster MS of multiple myeloma samples with characteristic expression spike of WHSC1 [GeneID=7468].

description_full:
[cell repeats an earlier one in this file: 1481 characters]


systematic_name: M10412
exact_source: Table 3S: Subgroup = PR
source_species_code: HS
GEO_id: GSE2658
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top 50 down-regulated genes in cluster PR of multiple myeloma samples characterized by increased expression of proliferation and cell cycle genes.

description_full:
[cell repeats an earlier one in this file: 1481 characters]


systematic_name: M17937
exact_source: Table 3S: 1st PCA genes (-)
source_species_code: HS
GEO_id: GSE6481
contributor: Nikolaos Papanikolaou
contrib_organization: Aristoteles University of Thessaloniki
description_brief:
  Top 100 probe sets contrubuting to the negative side of the 1st principal component; predominantly associated with synovial sarcoma and myxoid/round cell liposarcoma samples.

description_full:
  In soft tissue sarcomas, the diagnosis of malignant fibrous histiocytoma (MFH) has been a very controversial issue, and MFH is now considered to be reclassified into pleomorphic subtypes of other sarcomas. To characterize MFH genetically, we used an oligonucleotide microarray to analyze gene expression in 105 samples from 10 types of soft tissue tumors. Spindle cell and pleomorphic sarcomas, such as dedifferentiated liposarcoma, myxofibrosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor (MPNST), fibrosarcoma and MFH, showed similar gene expression patterns compared to other tumors. Samples from those five sarcoma types could be classified into respective clusters based on gene expression by excluding MFH samples. We calculated distances between MFH samples and other five sarcoma types (dedifferentiated liposarcoma, myxofibrosarcoma, leiomyosarcoma, MPNST and fibrosarcoma) based on differentially expressed genes and evaluated similarities. Three of the 21 MFH samples showed marked similarities to one of the five sarcoma types, which were supported by histological findings. Although most of the remaining 18 MFH samples showed little or no histological resemblance to one of the five sarcoma types, 12 of them showed moderate similarities in terms of gene expression. These results explain the heterogeneity of MFH and show that the majority of MFHs could be reclassified into pleomorphic subtypes of other sarcomas. Taken together, gene expression profiling could be a useful tool to unveil the difference in the underlying molecular backgrounds, which leads to a rational taxonomy and diagnosis of a diverse group of soft tissue sarcomas.


systematic_name: M18742
exact_source: Table 8S
source_species_code: HS
GEO_id: GSE12452
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes whose reduced expression in nasopharyngeal carinoma (NPC) correlated most with the increased expression of EBNA1 [GeneID=3783774], a latent gene of Epstein-Barr virus (EBV).

description_full:
  To identify the molecular mechanisms by which EBV-associated epithelial cancers are maintained, we measured the expression of essentially all human genes and all latent EBV genes in a collection of 31 laser-captured, microdissected nasopharyngeal carcinoma (NPC) tissue samples and 10 normal nasopharyngeal tissues. Global gene expression profiles clearly distinguished tumors from normal healthy epithelium. Expression levels of six viral genes (EBNA1, EBNA2, EBNA3A, EBNA3B, LMP1, and LMP2A) were correlated among themselves and strongly inversely correlated with the expression of a large subset of host genes. Among the human genes whose inhibition was most strongly correlated with increased EBV gene expression were multiple MHC class I HLA genes involved in regulating immune response via antigen presentation. The association between EBV gene expression and inhibition of MHC class I HLA expression implies that antigen display is either directly inhibited by EBV, facilitating immune evasion by tumor cells, and/or that tumor cells with inhibited presentation are selected for their ability to sustain higher levels of EBV to take maximum advantage of EBV oncogene-mediated tumor-promoting actions. Our data clearly reflect such tumor promotion, showing that deregulation of key proteins involved in apoptosis (BCL2-related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1, and NIN), and metastasis (matrix metalloproteinase 1) is closely correlated with the levels of EBV gene expression in NPC.


systematic_name: M2023
exact_source: Table 1: Cluster 5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes in cluster 5: slowly down-regulated in HFW cells (fibroblast) by sodium arsenite [PubChem=26435].

description_full:
  Arsenic compounds are widely distributed and arsenic ingestion is associated with many human diseases, including blackfoot disease, atherosclerosis, and cancers. However, the underlying mechanism of arsenic toxicity is not understood. In human fibroblast cells (HFW), arsenite is known to induce oxidative damage, chromosome aberrations, cell cycle arrest, and aneuploidy, and the manifestation of these cellular responses is dependent on changes in gene expression which can be analyzed using the cDNA microarray technique. In this study, cDNA microarray membranes with 568 human genes were used to examine mRNA profile changes in HFW cells treated for 0 to 24 h with 5 microM sodium arsenite. On the basis of the mean value for three independent experiments, 133 target genes were selected for a 2 x 3 self-organizing map cluster analysis; 94 were found to be induced by arsenite treatment, whereas 39 were repressed. These genes were categorized as signal transduction, transcriptional regulation, cell cycle control, stress responses, proteolytic enzymes, and miscellaneous. Significant changes in the signaling-related and transcriptional regulation genes indicated that arsenite induces complex toxicopathological injury.


systematic_name: M2024
exact_source: Fig.2: % of change >80% at days 1,3 or 5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in mesenchymal stem cells during early phase of adipogenesis, defined as days 1 to 5 of culturing with adipogenic hormones.

description_full:
  Human bone marrow mesenchymal stem cells (hMSCs) give rise to adipocytes in response to adipogenic hormones. An in-house cDNA microarray representing 3400 genes was employed to characterize the modulation of genes involved in this process. A total of 197 genes showed temporal gene expression changes during adipogenesis, including genes encoding transcriptional regulators and signaling molecules. Semi-quantitative RT-PCR analyses confirmed differential expression at the transcriptional level of several genes identified by cDNA microarray screening. Cluster analysis of the genes regulated during the late phase (from day 7 to day 14) of hMSC adipogenesis indicated that these changes are well correlated with data previously reported for murine preadipocytes. However, during the early phase (day 1-day 5), the modulations of genes differed from those reported for the preadipocytes. These data provide novel information on the molecular mechanisms required for lineage commitment and maturation accompanying adipogenesis of hMSC.


systematic_name: M2026
exact_source: Fig.2: % of change >80% at days 7,9 or 14
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in mesenchymal stem cells during late phase of adipogenesis, defined as days 7 to 14 of culturing with adipogenic hormones.

description_full:
  Human bone marrow mesenchymal stem cells (hMSCs) give rise to adipocytes in response to adipogenic hormones. An in-house cDNA microarray representing 3400 genes was employed to characterize the modulation of genes involved in this process. A total of 197 genes showed temporal gene expression changes during adipogenesis, including genes encoding transcriptional regulators and signaling molecules. Semi-quantitative RT-PCR analyses confirmed differential expression at the transcriptional level of several genes identified by cDNA microarray screening. Cluster analysis of the genes regulated during the late phase (from day 7 to day 14) of hMSC adipogenesis indicated that these changes are well correlated with data previously reported for murine preadipocytes. However, during the early phase (day 1-day 5), the modulations of genes differed from those reported for the preadipocytes. These data provide novel information on the molecular mechanisms required for lineage commitment and maturation accompanying adipogenesis of hMSC.


systematic_name: M15374
exact_source: Table 1: Cluster 6
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 6: ECM related genes up-regulated in dermal fibroblasts later than 30 min after TGFB1 [GeneID=7040] addition; slowly increased up to 120 min time point, then reached a plateau.

description_full:
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description_brief: Gene expression signature of vascular invasion of hepatocellular carcinoma (HCC).
systematic_name: M8773
exact_source: Fig. 2
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_full:
  BACKGROUND: Recurrence after hepatocellular carcinoma (HCC) resection is the major obstacle to improved survival. The presence of vascular invasion (VI) in pathology specimens is a well-known unfavorable prognostic factor for HCC recurrence. Though some VI-related genes have been reported, their association with recurrence-free survival is not known. We hypothesized that a gene expression profile for VI can predict the recurrence of HCC after liver resection. METHODS: Eighteen patients receiving complete HCC resection were included as a training group. Genome-wide gene expression profile was obtained for each tumor using a microarray technique. Datasets were subjected to clustering analysis supervised by the presence or absence of VI to obtain 14 discriminative genes. We then applied those genes to execute pattern recognition using the k-Nearest Neighbor (KNN) classification method, and the best model for this VI gene signature to predict recurrence-free survival in the training group was obtained. The resulting model was then tested in an independent test group of 35 patients. RESULTS: A 14-gene profile was extracted which could accurately separate ten patients with VI and eight patients without VI in the training group. In the test group, significant difference in disease-free survival was found between patients predicted to have and not to have recurrence (P = .02823). In patients with stage_I disease, this model can also predict outcomes (P = .000205). CONCLUSIONS: Using the 14-gene expression profile extracted from microarrays based on the presence of VI can effectively predict recurrence after HCC resection. This approach might facilitate personalized medicine for HCC patients after surgical resection.


systematic_name: M2045
exact_source: Suppl. Fle 2: cluster 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 1: genes up-regulated in SW260 cells (colon cancer) by sodium butyrate, curcumin, sulindac and TSA [PubChem=5222465;969516;5352;5562].

description_full:
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systematic_name: M2046
exact_source: Suppl. File 2: cluster 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 2: genes up-regulated in SW260 cells (colon cancer) by sodium butyrate, curcumin, sulindac and TSA [PubChem=5222465;969516;5352;5562].

description_full:
[cell repeats an earlier one in this file: 2217 characters]


systematic_name: M2047
exact_source: Table 2: Cluster 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in response to hydorgen peroxyde [PubChem=784] in CS-B cells (Cockaine syndrome fibroblast, CS) with defficient ERCC6 [GeneID=2074].

description_full:
  Cockayne syndrome (CS) is a human hereditary disease belonging to the group of segmental progerias, and the clinical phenotype is characterized by postnatal growth failure, neurological dysfunction, cachetic dwarfism, photosensitivity, sensorineural hearing loss, and retinal degradation. CS-B cells are defective in transcription-coupled DNA repair, base excision repair, transcription, and chromatin structural organization. Using array analysis, we have examined the expression profile in CS complementation group B (CS-B) fibroblasts after exposure to oxidative stress (H2O2) before and after complete complementation with the CSB gene. The following isogenic cell lines were compared: CS-B cells (CS-B null), CS-B cells complemented with wild-type CSB (CS-B wt), and a stably transformed cell line with a point mutation in the ATPase domain of CSB (CS-B ATPase mutant). In the wt rescued cells, we detected significant induction (two-fold) of 112 genes out of the 6912 analysed. The patterns suggested an induction or upregulation of genes involved in several DNA metabolic processes including DNA repair, transcription, and signal transduction. In both CS-B mutant cell lines, we found a general deficiency in transcription after oxidative stress, suggesting that the CSB protein influenced the regulation of transcription of certain genes. Of the 6912 genes, 122 were differentially regulated by more than two-fold. Evidently, the ATPase function of CSB is biologically important as the deficiencies seen in the ATPase mutant cells are very similar to those observed in the CS-B-null cells. Some major defects are in the transcription of genes involved in DNA repair, signal transduction, and ribosomal functions.


systematic_name: M2048
exact_source: Table 2: Clusters 2 & 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in response to hydorgen peroxyde [PubChem=784] in CS-B cells (Cockaine syndrome fibroblast, CS) with defficient ERCC6 [GeneID=2074].

description_full:
[cell repeats an earlier one in this file: 1720 characters]


systematic_name: M2050
exact_source: Table 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in peripheral lymphocytes from old individuals compared to those from young donors.

description_full:
[cell repeats an earlier one in this file: 1442 characters]


systematic_name: M5002
exact_source: Fig 6d
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster G24: genes induced in NHEK (normal keratinocyte) but not in SCC12B2 cells (squamous cell carcinoma) by UV-B radiation.

description_full:
  To gain insight into the transformation of epidermal cells into squamous carcinoma cells (SCC), we compared the response to ultraviolet B radiation (UVB) of normal human epidermal keratinocytes (NHEK) versus their transformed counterpart, SCC, using biological and molecular profiling. DNA microarray analyses (Affymetrix), approximately 12000 genes) indicated that the major group of upregulated genes in keratinocytes fall into three categories: (i). antiapoptotic and cell survival factors, including chemokines of the CXC/CC subfamilies (e.g. IL-8, GRO-1, -2, -3, SCYA20), growth factors (e.g. HB-EGF, CTGF, INSL-4), and proinflammatory mediators (e.g. COX-2, S100A9), (ii). DNA repair-related genes (e.g. GADD45, ERCC, BTG-1, Histones), and (iii). ECM proteases (MMP-1, -10). The major downregulated genes are DeltaNp63 and PUMILIO, two potential markers for the maintenance of keratinocyte stem cells. NHEK were found to be more resistant than SCC to UVB-induced apoptosis and this resistance was mainly because of the protection from cell death by secreted survival factors, since it can be transferred from NHEK to SCC cultures by the conditioned medium. Whereas the response of keratinocytes to UVB involved regulation of key checkpoint genes (p53, MDM2, p21(Cip1), DeltaNp63), as well as antiapoptotic and DNA repair-related genes - no or little regulation of these genes was observed in SCC. The effect of UVB on NHEK and SCC resulted in upregulation of 251 and 127 genes, respectively, and downregulation of 322 genes in NHEK and 117 genes in SCC. To further analyse these changes, we used a novel unsupervised coupled two-way clustering method that allowed the identification of groups of genes that clearly partitioned keratinocytes from SCC, including a group of genes whose constitutive expression levels were similar before UVB. This allowed the identification of discriminating genes not otherwise revealed by simple static comparison in the absence of UVB irradiation. The implication of the changes in gene profile in keratinocytes for epithelial cancer is discussed.


systematic_name: M15132
exact_source: Table 3: 24 h up-regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in T98G cells (glioma, express MGMT [GeneID=4255]) by carmustine [PubChem=2578] at 24 h.

description_full:
[cell repeats an earlier one in this file: 1725 characters]


systematic_name: M2065
exact_source: Table 2: Fold change < 0
source_species_code: HS
GEO_id: GSE17766
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MCF7 cells (breast cancer) upon knockdown of CLOCK [GeneID=9575] by RNAi that also belong to the highest confidence network (according to Ingenuity Pathway Analysis).

description_full:
  The transcription factors responsible for maintaining circadian rhythm influence a variety of biological processes. Recently, it has been suggested that the core circadian genes may play a role in breast tumorigenesis, possibly by influencing hormone regulation or other pathways relevant to cancer. To evaluate this hypothesis, we conducted a genetic and epigenetic association study, as well as a transcriptional profiling array and a pathway-based network analysis. We report significant correlations between single nucleotide polymorphisms associated with the central circadian regulator CLOCK and breast cancer risk, with apparent effect modification by estrogen receptor/progesterone receptor status. We also found that hypermethylation in the CLOCK promoter reduced the risk of breast cancer, and lower levels of CLOCK expression were documented in healthy controls relative to normal or tumor tissue from patients with breast cancer. Finally, we silenced CLOCK in vitro and performed a whole-genome expression microarray and pathway analysis, which identified a cancer-relevant network of transcripts with altered expression following CLOCK gene knockdown. Our findings support the hypothesis that circadian genes influence tumorigenesis, and identify a set of circadian gene variants as candidate breast cancer susceptibility biomarkers.


systematic_name: M2522
exact_source: Table 2S: 38 genes
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in 786-0 cells (renal carcinoma, RCC) by the loss of VHL [GeneID=7428] and in response to hypoxia.

description_full:
  The von Hippel-Lindau tumor suppressor, pVHL, is a key player in one of the best characterized hypoxia signaling pathways, the VHL-hypoxia-inducible factor (VHL-HIF) pathway. To better understand the role of VHL in the hypoxia signaling pathways of tumor cells, we used serial analysis of gene expression (SAGE) to investigate hypoxia-regulated gene expression in renal carcinoma cells (786-0), with and without VHL. The gene expression profiles of the cancer cells were compared to SAGE profiles from normal renal proximal tubule cells grown under both normoxia and hypoxia. The data suggest that the role of VHL as a tumor suppressor may be more complex than previously thought. Further, the data reveal that renal carcinoma cells have evolved an alternative hypoxia signaling pathway(s) compared with normal renal cells. These alternative hypoxia pathways demonstrate VHL-dependent and VHL-independent regulation. The genes involved in such pathways include those with potential importance in the physiological and pathological regulation of tumor growth and angiogenesis. Some of the genes identified as showing overexpression in the cancer cells, particularly those encoding secreted or membrane-bound proteins, could be potential biomarkers for tumors or targets for rational therapeutics that are dependent on VHL status.


systematic_name: M2067
exact_source: Table 2: Upregulated genes
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MEF cells (embryonic fibroblast) lacking TP53 and BRCA1 [GeneID=7157;672] by expression of BRCA1.

description_full:
  The tumor suppressor protein BRCA1 has been shown to enhance p53 transcription, whereas activated p53 represses BRCA1 transcription. To further understand the functional interaction of these proteins, we investigated the role of BRCA1 in p53-induced phenotypes. We found that BRCA1 when subjected to forced expression acts synergistically with wild-type p53, resulting in irreversible growth arrest, as shown by VhD mouse fibroblast cells expressing a temperature-sensitive mutant of p53. Furthermore, reintroduction of both BRCA1 and p53 into BRCA1(-/-)/p53(-/-) mouse embryonic fibroblasts markedly increased the senescence phenotype compared to that induced by p53 alone. In particular, we found that BRCA1 expression attenuated p53-mediated cell death in response to gamma-irradiation. Moreover, microarray screening of 11 000 murine genes demonstrated that a set of genes upregulated by p53 is enhanced by coexpression of BRCA1 and p53, suggesting that BRCA1 and p53 exert a promoter selectivity leading to a specific phenotype. Taken together, our results provide evidence that BRCA1 is involved in p53-mediated growth suppression rather than apoptosis.


systematic_name: M16587
exact_source: Table 1-4: LH & FSH > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in primary granulosa cells after stimulation with LH or FSH gonadotrophic hormones for 24 h.

description_full:
  Gonadotrophins exert a major effect on ovarian development and on the control of fertilization. By stimulating cells with forskolin (FK), it is possible to study which genes are activated by gonadotrophins via the cAMP cascade, and which by alternative pathways. Using RNA isolated from stimulated cells, we found that 59% of the total genes modulated by LH were also modulated by FK, while 69% of the genes modulated exclusively by FSH were also modulated by FK. Gene transcripts involved in steroidogenesis/progesterone production were highly elevated, while 17beta-hydroxysteroid dehydrogenase was down-regulated. This suggests that a decrease in the conversion of androstenedione to testosterone and estrone to estradiol occurs during luteinization. Down-regulation of genes coding for actin cytoskeleton proteins and cytokeratin 18 was observed in response to gonadotrophin and cAMP stimulation. Several of the genes coding for the microtubule network were also modulated, implying that rearrangement of the cytoskeletal proteins permits better coupling between organelles involved in steroidogenesis. A dramatic change in gene transcripts coding for signalling enzymes was observed following LH stimulation. This includes the down-regulation of adenylyl cyclase 7 and 9, elevation of cAMP-dependent phosphodiesterase, and the up-regulation of a negative regulator of G-protein signalling (RGS16) that may negate gonadotrophin signalling via guanine nucleotide binding proteins. Thus luteinized cells, despite increased gene transcripts to LH/chorionic gonadotrophin (CG) receptors, respond inefficiently to gonadotrophin stimulation, due to attenuation of signal transduction in the cAMP cascade at multiple steps. Novel genes involved in the regulation of apoptosis were found for the first time to be up-regulated by gonadotrophin stimulation, including: BAX inhibitor-1, granulysin and apoptosis repressor with caspase recruitment domain (ARC). These proteins may be involved in a unique alternative pathway of ovarian cell death. Such a pathway could temporarily preserve the mitochondria and progesterone production during the initial stages of granulosa cell apoptosis.


systematic_name: M17143
exact_source: Table 1-4: LH & FSH < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in primary granulosa cells after stimulation with LH or FSH gonadotrophic hormones for 24 h.

description_full:
  Gonadotrophins exert a major effect on ovarian development and on the control of fertilization. By stimulating cells with forskolin (FK), it is possible to study which genes are activated by gonadotrophins via the cAMP cascade, and which by alternative pathways. Using RNA isolated from stimulated cells, we found that 59% of the total genes modulated by LH were also modulated by FK, while 69% of the genes modulated exclusively by FSH were also modulated by FK. Gene transcripts involved in steroidogenesis/progesterone production were highly elevated, while 17beta-hydroxysteroid dehydrogenase was down-regulated. This suggests that a decrease in the conversion of androstenedione to testosterone and estrone to estradiol occurs during luteinization. Down-regulation of genes coding for actin cytoskeleton proteins and cytokeratin 18 was observed in response to gonadotrophin and cAMP stimulation. Several of the genes coding for the microtubule network were also modulated, implying that rearrangement of the cytoskeletal proteins permits better coupling between organelles involved in steroidogenesis. A dramatic change in gene transcripts coding for signalling enzymes was observed following LH stimulation. This includes the down-regulation of adenylyl cyclase 7 and 9, elevation of cAMP-dependent phosphodiesterase, and the up-regulation of a negative regulator of G-protein signalling (RGS16) that may negate gonadotrophin signalling via guanine nucleotide binding proteins. Thus luteinized cells, despite increased gene transcripts to LH/chorionic gonadotrophin (CG) receptors, respond inefficiently to gonadotrophin stimulation, due to attenuation of signal transduction in the cAMP cascade at multiple steps. Novel genes involved in the regulation of apoptosis were found for the first time to be up-regulated by gonadotrophin stimulation, including: BAX inhibitor-1, granulysin and apoptosis repressor with caspase recruitment domain (ARC). These proteins may be involved in a unique alternative pathway of ovarian cell death. Such a pathway could temporarily preserve the mitochondria and progesterone production during the initial stages of granulosa cell apoptosis.


systematic_name: M2072
exact_source: Table 5: Increased by BRCA1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes concordantly up-regulated in DU-145 and MCF-7 cells (lprostate, breast cancer) upon expression of BRCA1.

description_full:
  Mutations of the breast cancer susceptibility gene 1 (BRCA1), a tumor suppressor, confer an increased risk for breast, ovarian, and prostate cancers. To investigate the function of the BRCA1 gene, we performed DNA microarray and confirmatory reverse transcription-PCR analyses to identify BRCA1-regulated gene expression changes. We found that BRCA1 up-regulates the expression of multiple genes involved in the cytoprotective antioxidant response, including glutathione S-transferases, oxidoreductases, and other antioxidant genes. Consistent with these findings, BRCA1 overexpression conferred resistance while BRCA1 deficiency conferred sensitivity to several different oxidizing agents (hydrogen peroxide and paraquat). In addition, in the setting of oxidative stress (due to hydrogen peroxide), BRCA1 shifted the cellular redox balance to a higher ratio of reduced to oxidized glutathione. Finally, BRCA1 stimulated antioxidant response element-driven transcriptional activity and enhanced the activity of the antioxidant response transcription factor nuclear factor erythroid-derived 2 like 2 [also called NRF2 (NFE2L2)]. The ability of BRCA1 to stimulate antioxidant response element-dependent transcription and to protect cells against oxidative stress was attenuated by inhibition of nuclear factor erythroid-derived 2 like 2. These findings suggest a novel function for BRCA1, i.e., to protect cells against oxidative stress. This function would be consistent with the postulated role of BRCA1 as a caretaker gene in preserving genomic integrity.


systematic_name: M2073
exact_source: Table 5: Decreased by BRCA1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes concordantly down-regulated in DU-145 and MCF-7 cells (lprostate, breast cancer) upon expression of BRCA1.

description_full:
  Mutations of the breast cancer susceptibility gene 1 (BRCA1), a tumor suppressor, confer an increased risk for breast, ovarian, and prostate cancers. To investigate the function of the BRCA1 gene, we performed DNA microarray and confirmatory reverse transcription-PCR analyses to identify BRCA1-regulated gene expression changes. We found that BRCA1 up-regulates the expression of multiple genes involved in the cytoprotective antioxidant response, including glutathione S-transferases, oxidoreductases, and other antioxidant genes. Consistent with these findings, BRCA1 overexpression conferred resistance while BRCA1 deficiency conferred sensitivity to several different oxidizing agents (hydrogen peroxide and paraquat). In addition, in the setting of oxidative stress (due to hydrogen peroxide), BRCA1 shifted the cellular redox balance to a higher ratio of reduced to oxidized glutathione. Finally, BRCA1 stimulated antioxidant response element-driven transcriptional activity and enhanced the activity of the antioxidant response transcription factor nuclear factor erythroid-derived 2 like 2 [also called NRF2 (NFE2L2)]. The ability of BRCA1 to stimulate antioxidant response element-dependent transcription and to protect cells against oxidative stress was attenuated by inhibition of nuclear factor erythroid-derived 2 like 2. These findings suggest a novel function for BRCA1, i.e., to protect cells against oxidative stress. This function would be consistent with the postulated role of BRCA1 as a caretaker gene in preserving genomic integrity.


description_brief: Genes in this set correspond to the most abuntant transcripts that are also specific to platelets.
systematic_name: M7732
exact_source: Table 2S: Relative Expression Index > 1
source_species_code: HS
GEO_id: GSE11524
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  BACKGROUND: In sickle cell disease, ischemia-reperfusion injury and intravascular hemolysis produce endothelial dysfunction and vasculopathy characterized by reduced nitric oxide and arginine bioavailability. Recent functional studies of platelets in patients with sickle cell disease reveal a basally activated state, which suggests that pathological platelet activation may contribute to sickle cell disease vasculopathy. METHODS AND RESULTS: Studies were therefore undertaken to examine transcriptional signaling pathways in platelets that may be dysregulated in sickle cell disease. We demonstrate and validate in the present study the feasibility of comparative platelet transcriptome studies on clinical samples from single donors by the application of RNA amplification followed by microarray-based analysis of 54,000 probe sets. Data mining an existing microarray database, we identified 220 highly abundant genes in platelets and a subset of 72 relatively platelet-specific genes, defined by >10-fold increased expression compared with the median of other cell types in the database with amplified transcripts. The highly abundant platelet transcripts found in the present study included 82% or 70% of platelet-abundant genes identified in 2 previous gene expression studies on nonamplified mRNA from pooled or apheresis samples, respectively. On comparing the platelet gene expression profiles in 18 patients with sickle cell disease in steady state to those of 12 black control subjects, at a 3-fold cutoff and 5% false-discovery rate, we identified approximately 100 differentially expressed genes, including multiple genes involved in arginine metabolism and redox homeostasis. Further characterization of these pathways with real-time polymerase chain reaction and biochemical assays revealed increased arginase II expression and activity and decreased platelet polyamine levels. CONCLUSIONS: The present studies suggest a potential pathogenic role for platelet arginase and altered arginine and polyamine metabolism in sickle cell disease and provide a novel framework for the study of disease-specific platelet biology.


systematic_name: M2083
exact_source: Table 2: ER-positive group, Cox < 0
source_species_code: HS
GEO_id: GSE2034
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression in primary ER(+) [GeneID=2099] breast cancer tumors negatively correlates with developing distant metastases.

description_full:
  BACKGROUND: Genome-wide measures of gene expression can identify patterns of gene activity that subclassify tumours and might provide a better means than is currently available for individual risk assessment in patients with lymph-node-negative breast cancer. METHODS: We analysed, with Affymetrix Human U133a GeneChips, the expression of 22000 transcripts from total RNA of frozen tumour samples from 286 lymph-node-negative patients who had not received adjuvant systemic treatment. FINDINGS: In a training set of 115 tumours, we identified a 76-gene signature consisting of 60 genes for patients positive for oestrogen receptors (ER) and 16 genes for ER-negative patients. This signature showed 93% sensitivity and 48% specificity in a subsequent independent testing set of 171 lymph-node-negative patients. The gene profile was highly informative in identifying patients who developed distant metastases within 5 years (hazard ratio 5.67 [95% CI 2.59-12.4]), even when corrected for traditional prognostic factors in multivariate analysis (5.55 [2.46-12.5]). The 76-gene profile also represented a strong prognostic factor for the development of metastasis in the subgroups of 84 premenopausal patients (9.60 [2.28-40.5]), 87 postmenopausal patients (4.04 [1.57-10.4]), and 79 patients with tumours of 10-20 mm (14.1 [3.34-59.2]), a group of patients for whom prediction of prognosis is especially difficult. INTERPRETATION: The identified signature provides a powerful tool for identification of patients at high risk of distant recurrence. The ability to identify patients who have a favourable prognosis could, after independent confirmation, allow clinicians to avoid adjuvant systemic therapy or to choose less aggressive therapeutic options.


systematic_name: M2084
exact_source: Table 2: ER-negative group, Cox < 0
source_species_code: HS
GEO_id: GSE2034
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression in primary ER(-) [GeneID=2099] breast cancer tumors negatively correlates with developing distant metastases.

description_full:
  BACKGROUND: Genome-wide measures of gene expression can identify patterns of gene activity that subclassify tumours and might provide a better means than is currently available for individual risk assessment in patients with lymph-node-negative breast cancer. METHODS: We analysed, with Affymetrix Human U133a GeneChips, the expression of 22000 transcripts from total RNA of frozen tumour samples from 286 lymph-node-negative patients who had not received adjuvant systemic treatment. FINDINGS: In a training set of 115 tumours, we identified a 76-gene signature consisting of 60 genes for patients positive for oestrogen receptors (ER) and 16 genes for ER-negative patients. This signature showed 93% sensitivity and 48% specificity in a subsequent independent testing set of 171 lymph-node-negative patients. The gene profile was highly informative in identifying patients who developed distant metastases within 5 years (hazard ratio 5.67 [95% CI 2.59-12.4]), even when corrected for traditional prognostic factors in multivariate analysis (5.55 [2.46-12.5]). The 76-gene profile also represented a strong prognostic factor for the development of metastasis in the subgroups of 84 premenopausal patients (9.60 [2.28-40.5]), 87 postmenopausal patients (4.04 [1.57-10.4]), and 79 patients with tumours of 10-20 mm (14.1 [3.34-59.2]), a group of patients for whom prediction of prognosis is especially difficult. INTERPRETATION: The identified signature provides a powerful tool for identification of patients at high risk of distant recurrence. The ability to identify patients who have a favourable prognosis could, after independent confirmation, allow clinicians to avoid adjuvant systemic therapy or to choose less aggressive therapeutic options.


systematic_name: M2089
exact_source: Table 2S: SOMATIC, fisher.exact < 0.05
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes showing significantly elevated somatic mutation frequencies in proneural G-CIMP (a CpG island methylator phenotype) GBM (glyoblastoma multiforme) tumors.

description_full:
  We have profiled promoter DNA methylation alterations in 272 glioblastoma tumors in the context of The Cancer Genome Atlas (TCGA). We found that a distinct subset of samples displays concerted hypermethylation at a large number of loci, indicating the existence of a glioma-CpG island methylator phenotype (G-CIMP). We validated G-CIMP in a set of non-TCGA glioblastomas and low-grade gliomas. G-CIMP tumors belong to the proneural subgroup, are more prevalent among lower-grade gliomas, display distinct copy-number alterations, and are tightly associated with IDH1 somatic mutations. Patients with G-CIMP tumors are younger at the time of diagnosis and experience significantly improved outcome. These findings identify G-CIMP as a distinct subset of human gliomas on molecular and clinical grounds.


systematic_name: M2090
exact_source: Table 2S: GERMLINE, fisher.exact < 0.05
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes with significantl germline mutation differences in proneural G-CIMP (a CpG island methylator phenotype) GBM (glyoblastoma multiforme) tumors.

description_full:
  We have profiled promoter DNA methylation alterations in 272 glioblastoma tumors in the context of The Cancer Genome Atlas (TCGA). We found that a distinct subset of samples displays concerted hypermethylation at a large number of loci, indicating the existence of a glioma-CpG island methylator phenotype (G-CIMP). We validated G-CIMP in a set of non-TCGA glioblastomas and low-grade gliomas. G-CIMP tumors belong to the proneural subgroup, are more prevalent among lower-grade gliomas, display distinct copy-number alterations, and are tightly associated with IDH1 somatic mutations. Patients with G-CIMP tumors are younger at the time of diagnosis and experience significantly improved outcome. These findings identify G-CIMP as a distinct subset of human gliomas on molecular and clinical grounds.


systematic_name: M2091
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top 50 most differentially hypermethylated and down-regulated genes in proneural G-CIMP (a CpG island methylator phenotype) GBM (glyoblastoma multiforme) tumors.

description_full:
  We have profiled promoter DNA methylation alterations in 272 glioblastoma tumors in the context of The Cancer Genome Atlas (TCGA). We found that a distinct subset of samples displays concerted hypermethylation at a large number of loci, indicating the existence of a glioma-CpG island methylator phenotype (G-CIMP). We validated G-CIMP in a set of non-TCGA glioblastomas and low-grade gliomas. G-CIMP tumors belong to the proneural subgroup, are more prevalent among lower-grade gliomas, display distinct copy-number alterations, and are tightly associated with IDH1 somatic mutations. Patients with G-CIMP tumors are younger at the time of diagnosis and experience significantly improved outcome. These findings identify G-CIMP as a distinct subset of human gliomas on molecular and clinical grounds.


systematic_name: M2098
exact_source: Table S6 upregulated genes
source_species_code: HS
GEO_id: GSE18886
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in NB4 cells (acute promyelocytic leukemia, APL) in response to tretinoin [PubChem=444795]; based on Chip-seq data.

description_full:
  Many different molecular mechanisms have been associated with PML-RARalpha-dependent transformation of hematopoietic progenitors. Here, we identified high confidence PML-RARalpha binding sites in an acute promyelocytic leukemia (APL) cell line and in two APL primary blasts. We found colocalization of PML-RARalpha with RXR to the vast majority of these binding regions. Genome-wide epigenetic studies revealed that treatment with pharmacological doses of all-trans retinoic acid induces changes in H3 acetylation, but not H3K27me3, H3K9me3, or DNA methylation at the PML-RARalpha/RXR binding sites or at nearby target genes. Our results suggest that PML-RARalpha/RXR functions as a local chromatin modulator and that specific recruitment of histone deacetylase activities to genes important for hematopoietic differentiation, RAR signaling, and epigenetic control is crucial to its transforming potential.


systematic_name: M2100
exact_source: Table 1
source_species_code: HS
GEO_id: E-MEXP-2538
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Gene promoters preferentially bound by a mutated form of TP53 [GeneID=7157] in SKBR3 cells (breast cancer).

description_full:
  The p53 gene is mutated in many human tumors. Cells of such tumors often contain abundant mutant p53 (mutp53) protein, which may contribute actively to tumor progression via a gain-of-function mechanism. We applied ChIP-on-chip analysis and identified the vitamin D receptor (VDR) response element as overrepresented in promoter sequences bound by mutp53. We report that mutp53 can interact functionally and physically with VDR. Mutp53 is recruited to VDR-regulated genes and modulates their expression, augmenting the transactivation of some genes and relieving the repression of others. Furthermore, mutp53 increases the nuclear accumulation of VDR. Importantly, mutp53 converts vitamin D into an antiapoptotic agent. Thus, p53 status can determine the biological impact of vitamin D on tumor cells.


systematic_name: M2106
exact_source: Table 1S: correlation coefficient < 0
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression was significantly and negatively correlated with the number of perineuronal oligodendrocytes in the layer III of BA9 brain region.

description_full:
  Cytoarchitectural abnormalities have been described in the prefrontal cortex of subjects with schizophrenia, bipolar disorder and depression. However, little is known about the gene expression profiles associated with these abnormalities. Genome-wide expression profiling technology provides an unbiased approach to identifying candidate genes and biological processes that may be associated with complex biological traits such as cytoarchitecture. In this study, we explored expression profiles associated with the abnormalities by using publicly available microarray metadata and cytoarchitectural data from post-mortem samples of the frontal cortex from 54 subjects (schizophrenia, n=14; bipolar disorder, n=13; depression, n=12 and controls n=15). Correlation analysis between genome-wide expression levels and cytoarchitectural traits revealed that 818 genes were significantly correlated with a decrease in the number of perineuronal oligodendrocytes across all subjects. A total of 600 genes were significantly correlated with a decrease in density of calbindin-positive interneurons across all subjects. Multiple biological processes including cellular metabolism, central nervous system development, cell motility and programmed cell death were significantly overrepresented in both correlated gene lists. These findings may provide novel insights into the molecular mechanisms that underlie the cytoarchitectural abnormalities of perineuronal oligodendrocytes and calbindin-containing GABAergic interneurons in the prefrontal cortex of the major psychiatric disorders.


systematic_name: M2109
exact_source: Table 2S: correlation coefficient < 0
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression significantly and negatively correlated with oligodendrocyte density in layer VI of BA9 brain region in patients with bipolar disorder.

description_full:
  Cytoarchitectural abnormalities have been described in the prefrontal cortex of subjects with schizophrenia, bipolar disorder and depression. However, little is known about the gene expression profiles associated with these abnormalities. Genome-wide expression profiling technology provides an unbiased approach to identifying candidate genes and biological processes that may be associated with complex biological traits such as cytoarchitecture. In this study, we explored expression profiles associated with the abnormalities by using publicly available microarray metadata and cytoarchitectural data from post-mortem samples of the frontal cortex from 54 subjects (schizophrenia, n=14; bipolar disorder, n=13; depression, n=12 and controls n=15). Correlation analysis between genome-wide expression levels and cytoarchitectural traits revealed that 818 genes were significantly correlated with a decrease in the number of perineuronal oligodendrocytes across all subjects. A total of 600 genes were significantly correlated with a decrease in density of calbindin-positive interneurons across all subjects. Multiple biological processes including cellular metabolism, central nervous system development, cell motility and programmed cell death were significantly overrepresented in both correlated gene lists. These findings may provide novel insights into the molecular mechanisms that underlie the cytoarchitectural abnormalities of perineuronal oligodendrocytes and calbindin-containing GABAergic interneurons in the prefrontal cortex of the major psychiatric disorders.


systematic_name: M2111
exact_source: Table 3S: correlation coefficient < 0
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression significantly and negatively correlated with the density of CALB1-positive [GeneID=793]  GABAergic interneurons in the BA9 brain region across all subjects with psychiatric disorders.

description_full:
  Cytoarchitectural abnormalities have been described in the prefrontal cortex of subjects with schizophrenia, bipolar disorder and depression. However, little is known about the gene expression profiles associated with these abnormalities. Genome-wide expression profiling technology provides an unbiased approach to identifying candidate genes and biological processes that may be associated with complex biological traits such as cytoarchitecture. In this study, we explored expression profiles associated with the abnormalities by using publicly available microarray metadata and cytoarchitectural data from post-mortem samples of the frontal cortex from 54 subjects (schizophrenia, n=14; bipolar disorder, n=13; depression, n=12 and controls n=15). Correlation analysis between genome-wide expression levels and cytoarchitectural traits revealed that 818 genes were significantly correlated with a decrease in the number of perineuronal oligodendrocytes across all subjects. A total of 600 genes were significantly correlated with a decrease in density of calbindin-positive interneurons across all subjects. Multiple biological processes including cellular metabolism, central nervous system development, cell motility and programmed cell death were significantly overrepresented in both correlated gene lists. These findings may provide novel insights into the molecular mechanisms that underlie the cytoarchitectural abnormalities of perineuronal oligodendrocytes and calbindin-containing GABAergic interneurons in the prefrontal cortex of the major psychiatric disorders.


systematic_name: M2112
exact_source: Table 6S: correlation coefficient > 0
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression in brain significantly and positively correlated with the duration of all psychiatric disorders studied.

description_full:
[cell repeats an earlier one in this file: 1578 characters]


description_brief: Genes correlated with proneural type of glioblastoma multiforme tumors.
systematic_name: M2115
exact_source: TCGA_unified_CORE_ClaNC840.txt GO genes = PN
external_details_URL: https://tcga-data.nci.nih.gov/docs/publications/gbm_2010/
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.


systematic_name: M2124
exact_source: Table 3S: Downregulated
source_species_code: HS
GEO_id: GSE17941
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in the cancer gene signature, representing a gene signature of cellular transformation.

description_full:
  Transcriptional profiling of two isogenic models of transformation identifies a gene signature linking cancer with inflammatory and metabolic diseases. In accord with this common transcriptional program, many drugs used for treatment of diabetes and cardiovascular diseases inhibit transformation and tumor growth. Unexpectedly, lipid metabolism genes are important for transformation and are upregulated in cancer tissues. As in atherosclerosis, oxidized LDL and its receptor OLR1 activate the inflammatory pathway through NF-kappaB, leading to transformation. OLR1 is important for maintaining the transformed state in developmentally diverse cancer cell lines and for tumor growth, suggesting a molecular connection between cancer and atherosclerosis. We suggest that the interplay between this common transcriptional program and cell-type-specific factors gives rise to phenotypically disparate human diseases.


systematic_name: M2126
exact_source: Table 2S: lowserum_shRb_up
source_species_code: HS
GEO_id: GSE19899
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in IMR90 cells (fibroblast) grown under low serum conditions and after knockdown of RB1 [GeneID=5925] by RNAi.

description_full:
  The RB protein family (RB, p107, and p130) has overlapping and compensatory functions in cell-cycle control. However, cancer-associated mutations are almost exclusively found in RB, implying that RB has a nonredundant role in tumor suppression. We demonstrate that RB preferentially associates with E2F target genes involved in DNA replication and is uniquely required to repress these genes during senescence but not other growth states. Consequently, RB loss leads to inappropriate DNA synthesis following a senescence trigger and, together with disruption of a p21-mediated cell-cycle checkpoint, enables extensive proliferation and rampant genomic instability. Our results identify a nonredundant RB effector function that may contribute to tumor suppression and reveal how loss of RB and p53 cooperate to bypass senescence.


systematic_name: M2131
exact_source: Table 2S: Upregulated genes
source_species_code: HS
GEO_id: GSE19736
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in RS4;11 cells (MLL, mixed lineage leukemia) in response to SB216763 [PubChem=176158], an inhibitor of GSK3B [GeneID=2932].

description_full:
  Acute leukemias induced by MLL chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on GSK-3 kinase activity for sustained proliferation. We demonstrate here that GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation. This mechanism also applies to hematopoietic cells transformed by other HOX genes, including CDX2, which is highly expressed in a majority of acute myeloid leukemias, thus providing a molecular approach based on GSK-3 inhibitory strategies to target HOX-associated transcription in a broad spectrum of leukemias.


description_brief: Genes up-regulated in SKOV3ip1 cells (ovarian cancer) upon knockdown of EZH2 [GeneID=2146] by RNAi.
systematic_name: M2139
exact_source: Fig 5SJ: personal communication
source_species_code: HS
GEO_id: GSE20381
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibited angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth, which is further enhanced in combination with ezh2 silencing in tumor cells. Collectively, these data support the potential for targeting ezh2 as an important therapeutic approach.


description_brief: Genes up-regulated in SH-SY5Y cells (neuroblastoma) after knockdown of NF1 [GeneID=4763] by RNAi.
systematic_name: M2142
exact_source: Table 1S: Log Ratio (vs pRS) > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Retinoic acid (RA) induces differentiation of neuroblastoma cells in vitro and is used with variable success to treat aggressive forms of this disease. This variability in clinical response to RA is enigmatic, as no mutations in components of the RA signaling cascade have been found. Using a large-scale RNAi genetic screen, we identify crosstalk between the tumor suppressor NF1 and retinoic acid-induced differentiation in neuroblastoma. Loss of NF1 activates RAS-MEK signaling, which in turn represses ZNF423, a critical transcriptional coactivator of the retinoic acid receptors. Neuroblastomas with low levels of both NF1 and ZNF423 have extremely poor outcome. We find NF1 mutations in neuroblastoma cell lines and in primary tumors. Inhibition of MEK signaling downstream of NF1 restores responsiveness to RA, suggesting a therapeutic strategy to overcome RA resistance in NF1-deficient neuroblastomas.


description_brief: Genes consistently underexpressed with age, based on meta-analysis of microarray data.
systematic_name: M2145
exact_source: http://genomics.senescence.info/genes/microarray.php?show=4&sort=1&page=1 Underexpressed
source_species_code: HS
contributor: João Pedro de Magalhaães
contrib_organization: University of Liverpool
description_full:
  MOTIVATION: Numerous microarray studies of aging have been conducted, yet given the noisy nature of gene expression changes with age, elucidating the transcriptional features of aging and how these relate to physiological, biochemical and pathological changes remains a critical problem. RESULTS: We performed a meta-analysis of age-related gene expression profiles using 27 datasets from mice, rats and humans. Our results reveal several common signatures of aging, including 56 genes consistently overexpressed with age, the most significant of which was APOD, and 17 genes underexpressed with age. We characterized the biological processes associated with these signatures and found that age-related gene expression changes most notably involve an overexpression of inflammation and immune response genes and of genes associated with the lysosome. An underexpression of collagen genes and of genes associated with energy metabolism, particularly mitochondrial genes, as well as alterations in the expression of genes related to apoptosis, cell cycle and cellular senescence biomarkers, were also observed. By employing a new method that emphasizes sensitivity, our work further reveals previously unknown transcriptional changes with age in many genes, processes and functions. We suggest these molecular signatures reflect a combination of degenerative processes but also transcriptional responses to the process of aging. Overall, our results help to understand how transcriptional changes relate to the process of aging and could serve as targets for future studies. AVAILABILITY: http://genomics.senescence.info/uarrays/signatures.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


description_brief: Cluster 1 of aberrantly hypermethylated genes in blasts from AML (acute myeloid leukemia) patients.
systematic_name: M2159
exact_source: Table 3AS: Hypermethylated
source_species_code: HS
GEO_id: GSE18700
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates).


description_brief: Genes encoding mRNA transcripts specifically bound by DCP2 [GeneID=167227].
systematic_name: M2188
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  mRNA decapping is a critical step in the control of mRNA stability and gene expression and is carried out by the Dcp2 decapping enzyme. Dcp2 is an RNA binding protein that must bind RNA in order to recognize the cap for hydrolysis. We demonstrate that human Dcp2 (hDcp2) preferentially binds to a subset of mRNAs and identify sequences at the 5' terminus of the mRNA encoding Rrp41, a core subunit component of the RNA exosome, as a specific hDcp2 substrate. A 60-nucleotide element at the 5' end of Rrp41 mRNA was identified and shown to confer more efficient decapping on a heterologous RNA both in vitro and upon transfection into cells. Moreover, reduction of hDcp2 protein levels in cells resulted in a selective stabilization of the Rrp41 mRNA, confirming it as a downstream target of hDcp2 regulation. These findings demonstrate that hDcp2 can specifically bind to and regulate the stability of a subset of mRNAs, and its intriguing regulation of the 3'-to-5' exonuclease exosome subunit suggests a potential interplay between 5'-end mRNA decapping and 3'-end mRNA decay.


description_brief: Genes responding to progestin R5020 [PubChem=36709] treatment of T47D-MTVL cells (breast cancer).
systematic_name: M2191
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE9286
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Steroid hormone receptors regulate gene expression, interacting with target DNA sequences but also activating cytoplasmic signaling pathways. Using the human 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) gene as a model, we have investigated the contributions of both effects on a human progesterone-responsive promoter in breast cancer cells. Chromatin immunoprecipitation has identified two different mechanisms of hormone-induced progesterone receptor (PR) recruitment to the 11beta-HSD2 promoter: (i) direct PR binding to DNA at the proximal promoter, abrogated when PR contains a mutated DNA binding domain (DBD), and (ii) STAT5A (signal transducer and activator of transcription 5A)-mediated recruitment of PR to an upstream distal region, impaired by AG490, a JAK/STAT pathway inhibitor. The JAK/STAT inhibitor, as well as expression of dominant-negative STAT5A, impairs hormone induction of 11beta-HSD2. On the other hand, the DBD-mutated PR fully supports 11beta-HSD2 expression. These results, along with data from a deletion analysis, indicate that the distal region is crucial for hormone regulation of 11beta-HSD2. We show active RNA polymerase II tracking from the distal region upon PR and STAT5A binding, concomitant with synthesis of noncoding, hormone-dependent RNAs, suggesting that this region works as a hormone-dependent transcriptional enhancer. In conclusion, coordination of PR transcriptional effects and cytoplasmic signaling activation, in particular the JAK/STAT pathway, are critical in regulating progestin-induced endogenous 11beta-HSD2 gene expression in breast cancer cells. This is not unique to this promoter, as AG490 also alters the expression of other progesterone-regulated genes.


description_brief: Genes significantly de-regulated (p < 0.05) by MIR21 [GeneID=406991] in A172 cells (glioma).
systematic_name: M2196
exact_source: Table 1S: mean p-value < 0.05
source_species_code: HS
GEO_id: GSE11778
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for physiological modulation of multiple proteins whose expression is deregulated in cancer.


description_brief: Genes bound and activated by ZNF217 [GeneID=7764] in MCF7 cells (breast cancer).
systematic_name: M2197
exact_source: Table 1: Genes activated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  The ZNF217 oncoprotein is a constituent of a core transcriptional complex that includes CoREST, histone deacetylase 1/2, lysine demethylase 1, and the C-terminal binding protein 1/2. We have combined genome-wide expression profiling and chromatin immunoprecipitation with directed selection and ligation (ChIP-DSL) to identify a subset of genes directly regulated by ZNF217. Our results establish p15(ink4b) as a direct target of the ZNF217 complex. Downregulation of ZNF217 in MCF-7 breast cancer cells resulted in a dramatic increase in p15(ink4b) expression and coincided with increases in dimethylation of H3-K4 and, surprisingly, a decrease in K9/K14-H3 acetylation. Stimulation of HaCaT cells with transforming growth factor beta (TGF-beta) resulted in a release of ZNF217 and a concomitant binding of SMAD2 to the proximal promoter, which preceded increases in ink4b protein expression. Furthermore, the changes in chromatin marks at the p15(ink4b) promoter following TGF-beta stimulation were similar to those observed following ZNF217 downregulation. Collectively, these results establish the ZNF217 complex as a novel negative regulator of the p15(ink4b) gene and may constitute an important link between amplification of ZNF217 and the loss of TGF-beta responsiveness in breast cancer.


description_brief: Potential targets of MIR302A [GeneID=407028].
systematic_name: M2208
exact_source: Fig. 4S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Oct4 and Sox2 are transcription factors required for pluripotency during early embryogenesis and for the maintenance of embryonic stem cell (ESC) identity. Functional mechanisms contributing to pluripotency are expected to be associated with genes transcriptionally activated by these factors. Here, we show that Oct4 and Sox2 bind to a conserved promoter region of miR-302, a cluster of eight microRNAs expressed specifically in ESCs and pluripotent cells. The expression of miR-302a is dependent on Oct4/Sox2 in human ESCs (hESCs), and miR-302a is expressed at the same developmental stages and in the same tissues as Oct4 during embryogenesis. miR-302a is predicted to target many cell cycle regulators, and the expression of miR-302a in primary and transformed cell lines promotes an increase in S-phase and a decrease in G(1)-phase cells, reminiscent of an ESC-like cell cycle profile. Correspondingly, the inhibition of miR-302 causes hESCs to accumulate in G(1) phase. Moreover, we show that miR-302a represses the productive translation of an important G(1) regulator, cyclin D1, in hESCs. The transcriptional activation of miR-302 and the translational repression of its targets, such as cyclin D1, may provide a link between Oct4/Sox2 and cell cycle regulation in pluripotent cells.


systematic_name: M2213
exact_source: Table 2S: Fold change STAT3A(1*6)-ER < 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in CD34+ [GeneID=947] cells by intermediate activity levels of STAT5A [GeneID=6776]; predominant long-term growth and self-renewal phenotype.

description_full:
  The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34(+) cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34(+) cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.


systematic_name: M2236
exact_source: Table 2S: Inc. in all 3
source_species_code: HS
GEO_id: GSE9747
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MDA-MB-231 cells (breast cancer) upon overexpression of PARVB [GeneID=29780] under all three culture conditions.

description_full:
  Parvin-beta is a focal adhesion protein downregulated in human breast cancer cells. Loss of Parvin-beta contributes to increased integrin-linked kinase activity, cell-matrix adhesion, and invasion through the extracellular matrix in vitro. The effect of ectopic Parvin-beta expression on the transcriptional profile of MDA-MB-231 breast cancer cells, which normally do not express Parvin-beta, was evaluated. Particular emphasis was placed upon propagating MDA-MB-231 breast cancer cells in three-dimensional culture matrices. Interestingly, Parvin-beta reexpression in MDA-MB-231 cells increased the mRNA expression, serine 82 phosphorylation (mediated by CDK9), and activity of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma), and there was a concomitant increase in lipogenic gene expression as a downstream effector of PPARgamma. Importantly, Parvin-beta suppressed breast cancer growth in vivo, with associated decreased proliferation. These data suggest that Parvin-beta might influence breast cancer progression.


systematic_name: M2237
exact_source: Table 2S: Dec. in all 3
source_species_code: HS
GEO_id: GSE9747
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MDA-MB-231 cells (breast cancer) upon overexpression of PARVB [GeneID=29780] under all three culture conditions.

description_full:
  Parvin-beta is a focal adhesion protein downregulated in human breast cancer cells. Loss of Parvin-beta contributes to increased integrin-linked kinase activity, cell-matrix adhesion, and invasion through the extracellular matrix in vitro. The effect of ectopic Parvin-beta expression on the transcriptional profile of MDA-MB-231 breast cancer cells, which normally do not express Parvin-beta, was evaluated. Particular emphasis was placed upon propagating MDA-MB-231 breast cancer cells in three-dimensional culture matrices. Interestingly, Parvin-beta reexpression in MDA-MB-231 cells increased the mRNA expression, serine 82 phosphorylation (mediated by CDK9), and activity of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma), and there was a concomitant increase in lipogenic gene expression as a downstream effector of PPARgamma. Importantly, Parvin-beta suppressed breast cancer growth in vivo, with associated decreased proliferation. These data suggest that Parvin-beta might influence breast cancer progression.


systematic_name: M2252
exact_source: File 8S: foglio2: promoters
source_species_code: HS
GEO_id: GSE6207,GSE8884,GSE6022
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Transcriptionally inactive genes whose promoters (regions between -2 kb to +0.5 kb relative to trascription start sites) where bound by NF-Y transcription factor.

description_full:
  NF-Y is a trimeric transcription factor containing H2A/H2B-like subunits, which specifically binds to the CCAAT box, a common eukaryotic promoter element. To gain insights into NF-Y-dependent transcriptional regulation, we assessed its relationships with positive histone marks by chromatin immunoprecipitation-on-chip and correlative-profiling studies. Unbiased identification of binding sites shows that the majority of genes are bound by NF-Y in the promoter and/or within the coding region. Parallel analysis of H3K9-14ac and H3K4me3 sites indicates that NF-Y loci can be divided in two distinct clusters: (i) a large cohort contains H3K9-14ac and H3K4me3 marks and correlates with expression and (ii) a sizeable group is devoid of these marks and is found on transcriptionally silent genes. Within this class, we find that NF-Y binding is associated with negative histone marks, such as H4K20me3 and H3K27me3. NF-Y removal by a dominant negative NF-YA leads to a decrease in the transcription of expressed genes associated with H3K4me3 and H3K9-14ac, while increasing the levels of many inactive genes. These data indicate that NF-Y is embedded in positive as well as in negative methyl histone marks, serving a dual function in transcriptional regulation, as an activator or as a repressor.


systematic_name: M2255
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE8596,GSE8665
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes commonly up-regulated in UET-13 cells (mesenchymal progenitor) by expression of EWSR1 [GeneID=2130] fusions with ETS transcription factors FLI1 and ERG [GeneID=2313 ,2078].

description_full:
  Ewing's family tumor (EFT) is a rare pediatric tumor of unclear origin that occurs in bone and soft tissue. Specific chromosomal translocations found in EFT cause EWS to fuse to a subset of ets transcription factor genes (ETS), generating chimeric EWS/ETS proteins. These proteins are believed to play a crucial role in the onset and progression of EFT. However, the mechanisms responsible for the EWS/ETS-mediated onset remain unclear. Here we report the establishment of a tetracycline-controlled EWS/ETS-inducible system in human bone marrow-derived mesenchymal progenitor cells (MPCs). Ectopic expression of both EWS/FLI1 and EWS/ERG proteins resulted in a dramatic change of morphology, i.e., from a mesenchymal spindle shape to a small round-to-polygonal cell, one of the characteristics of EFT. EWS/ETS also induced immunophenotypic changes in MPCs, including the disappearance of the mesenchyme-positive markers CD10 and CD13 and the up-regulation of the EFT-positive markers CD54, CD99, CD117, and CD271. Furthermore, a prominent shift from the gene expression profile of MPCs to that of EFT was observed in the presence of EWS/ETS. Together with the observation that EWS/ETS enhances the ability of cells to invade Matrigel, these results suggest that EWS/ETS proteins contribute to alterations of cellular features and confer an EFT-like phenotype to human MPCs.


description_brief: A consensus set of genes that were significantly down-regulated by MIR106B [GeneID=406900].
systematic_name: M2258
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE14831
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  microRNAs in the miR-106b family are overexpressed in multiple tumor types and are correlated with the expression of genes that regulate the cell cycle. Consistent with these observations, miR-106b family gain of function promotes cell cycle progression, whereas loss of function reverses this phenotype. Microarray profiling uncovers multiple targets of the family, including the cyclin-dependent kinase inhibitor p21/CDKN1A. We show that p21 is a direct target of miR-106b and that its silencing plays a key role in miR-106b-induced cell cycle phenotypes. We also show that miR-106b overrides a doxorubicin-induced DNA damage checkpoint. Thus, miR-106b family members contribute to tumor cell proliferation in part by regulating cell cycle progression and by modulating checkpoint functions.


systematic_name: M2263
exact_source: Fig. 8A
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Proteins significantly induced by oxidative stress (hydrogen peroxide [PubChem=784] in 786-O cells (renal clear cell carcinoma, RCC) expressing VHL [GeneID=7428].

description_full:
  Human renal clear cell carcinoma (RCC) is frequently associated with loss of the von Hippel-Lindau (VHL) tumor suppressor (pVHL), which inhibits ubiquitylation and degradation of the alpha subunits of hypoxia-inducible transcription factor. pVHL also ubiquitylates the large subunit of RNA polymerase II, Rpb1, phosphorylated on serine 5 (Ser5) within the C-terminal domain (CTD). A hydroxylated proline 1465 within an LXXLAP motif located N-terminal to the CTD allows the interaction of Rpb1 with pVHL. Here we report that in RCC cells, pVHL regulates expression of Rpb1 and is necessary for low-grade oxidative-stress-induced recruitment of Rpb1 to the DNA-engaged fraction and for its P1465 hydroxylation, phosphorylation, and nondegradative ubiquitylation. Egln-9-type prolyl hydroxylases, PHD1 and PHD2, coimmunoprecipitated with Rpb1 in the chromatin fraction of VHL(+) RCC cells in response to oxidative stress, and PHD1 was necessary for P1465 hydroxylation while PHD2 had an inhibitory effect. P1465 hydroxylation was required for oxidative-stress-induced Ser5 phosphorylation of Rpb1. Importantly, overexpression of wild-type Rpb1 stimulated formation of kidney tumors by VHL(+) cells, and this effect was abolished by P1465A mutation of Rpb1. These data indicate that through this novel pathway involving P1465 hydroxylation and Ser5 phosphorylation of Rbp1, pVHL may regulate tumor growth.


systematic_name: M2269
exact_source: Fig. 8B
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Proteins significantly repressed by oxidative stress (hydrogen peroxide [PubChem=784] in 786-O cells (renal clear cell carcinoma, RCC) expressing VHL [GeneID=7428].

description_full:
  Human renal clear cell carcinoma (RCC) is frequently associated with loss of the von Hippel-Lindau (VHL) tumor suppressor (pVHL), which inhibits ubiquitylation and degradation of the alpha subunits of hypoxia-inducible transcription factor. pVHL also ubiquitylates the large subunit of RNA polymerase II, Rpb1, phosphorylated on serine 5 (Ser5) within the C-terminal domain (CTD). A hydroxylated proline 1465 within an LXXLAP motif located N-terminal to the CTD allows the interaction of Rpb1 with pVHL. Here we report that in RCC cells, pVHL regulates expression of Rpb1 and is necessary for low-grade oxidative-stress-induced recruitment of Rpb1 to the DNA-engaged fraction and for its P1465 hydroxylation, phosphorylation, and nondegradative ubiquitylation. Egln-9-type prolyl hydroxylases, PHD1 and PHD2, coimmunoprecipitated with Rpb1 in the chromatin fraction of VHL(+) RCC cells in response to oxidative stress, and PHD1 was necessary for P1465 hydroxylation while PHD2 had an inhibitory effect. P1465 hydroxylation was required for oxidative-stress-induced Ser5 phosphorylation of Rpb1. Importantly, overexpression of wild-type Rpb1 stimulated formation of kidney tumors by VHL(+) cells, and this effect was abolished by P1465A mutation of Rpb1. These data indicate that through this novel pathway involving P1465 hydroxylation and Ser5 phosphorylation of Rbp1, pVHL may regulate tumor growth.


description_brief: Genes up-regulated in A549 cells (lung adenocarcinoma) upon SKIL [GeneID=6498] knockdown by RNAi.
systematic_name: M2273
exact_source: Table 2: Regulation=Up
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  SnoN is an important negative regulator of transforming growth factor beta signaling through its ability to interact with and repress the activity of Smad proteins. It was originally identified as an oncoprotein based on its ability to induce anchorage-independent growth in chicken embryo fibroblasts. However, the roles of SnoN in mammalian epithelial carcinogenesis have not been well defined. Here we show for the first time that SnoN plays an important but complex role in human cancer. SnoN expression is highly elevated in many human cancer cell lines, and this high level of SnoN promotes mitogenic transformation of breast and lung cancer cell lines in vitro and tumor growth in vivo, consistent with its proposed pro-oncogenic role. However, this high level of SnoN expression also inhibits epithelial-to-mesenchymal transdifferentiation. Breast and lung cancer cells expressing the shRNA for SnoN exhibited an increase in cell motility, actin stress fiber formation, metalloprotease activity, and extracellular matrix production as well as a reduction in adherens junction proteins. Supporting this observation, in an in vivo breast cancer metastasis model, reducing SnoN expression was found to moderately enhance metastasis of human breast cancer cells to bone and lung. Thus, SnoN plays both pro-tumorigenic and antitumorigenic roles at different stages of mammalian malignant progression. The growth-promoting activity of SnoN appears to require its ability to bind to and repress the Smad proteins, while the antitumorigenic activity can be mediated by both Smad-dependent and Smad-independent pathways and requires the activity of small GTPase RhoA. Our study has established the importance of SnoN in mammalian epithelial carcinogenesis and revealed a novel aspect of SnoN function in malignant progression.


systematic_name: M2278
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in synovial sarcoma samples with SYT-SSX fusions resulting from translocation of SS18 [GeneSymbol=SS18] to one of the SSX genes.

description_full:
  Chromosomal translocations are frequently associated with soft-tissue sarcomas. Fusion proteins generated by such translocations often play critical roles in tumorigenesis. Therefore, it is important to understand the function of the fusion protein to develop therapeutic interventions. The t(X;18)(p11.2;q11.2) translocation found in synovial sarcomas results in a fusion between the SYT gene on chromosome 18 and an SSX gene on the X chromosome. Although SYT-SSX fusion proteins appear to trigger synovial sarcoma development, little is known about the downstream targets of SYT-SSX. We found that the SYT-SSX fusion protein produces a dominant-negative function for SYT, which is a transcriptional coactivator. We then analyzed the gene expression profiles of SYT-SSX1-expressing HeLa cells using oligonucleotide microarrays and found that the SYT-SSX1 fusion protein directly down-regulated the expression of COM1, a regulator of cell proliferation. COM1 was found to be expressed at relatively low levels in synovial sarcoma tissues and cell lines. We then investigated the impact of conditional COM1 expression in the synovial sarcoma cell line. Increased COM1 expression resulted in induced apoptosis and in reduced cell growth and colony formation activity. Our results suggested that restoration of COM1 expression may be of therapeutic benefit in synovial sarcoma.


description_brief: Genes down-regulated in HeLa cells upon knockdown of MLL2 [GeneID=8085] by RNAi.
systematic_name: M2281
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  ALR (MLL2) is a member of the human MLL family, which belongs to a larger SET1 family of histone methyltransferases. We found that ALR is present within a stable multiprotein complex containing a cohort of proteins shared with other SET1 family complexes and several unique components, such as PTIP and the jumonji family member UTX. Like other complexes formed by SET1 family members, the ALR complex exhibited strong H3K4 methyltransferase activity, conferred by the ALR SET domain. By generating ALR knockdown cell lines and comparing their expression profiles to that of control cells, we identified a set of genes whose expression is activated by ALR. Some of these genes were identified by chromatin immunoprecipitation as direct ALR targets. The ALR complex was found to associate in an ALR-dependent fashion with promoters and transcription initiation sites of target genes and to induce H3K4 trimethylation. The most characteristic features of the ALR knockdown cells were changes in the dynamics and mode of cell spreading/polarization, reduced migration capacity, impaired anchorage-dependent and -independent growth, and decreased tumorigenicity in mice. Taken together, our results suggest that ALR is a transcriptional activator that induces the transcription of target genes by covalent histone modification. ALR appears to be involved in the regulation of adhesion-related cytoskeletal events, which might affect cell growth and survival.


systematic_name: M2284
exact_source: Table 4S
source_species_code: HS
GEO_id: GSE6838
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Transcripts down-regulated by overexpression of MIR16 family of microRNA molecules in DLD-1 and HCT116 (colon cancer) cells hypomorphic for DICER1 [GeneID=23405].

description_full:
  microRNAs (miRNAs) are abundant, approximately 21-nucleotide, noncoding regulatory RNAs. Each miRNA may regulate hundreds of mRNA targets, but the identities of these targets and the processes they regulate are poorly understood. Here we have explored the use of microarray profiling and functional screening to identify targets and biological processes triggered by the transfection of human cells with miRNAs. We demonstrate that a family of miRNAs sharing sequence identity with miRNA-16 (miR-16) negatively regulates cellular growth and cell cycle progression. miR-16-down-regulated transcripts were enriched with genes whose silencing by small interfering RNAs causes an accumulation of cells in G(0)/G(1). Simultaneous silencing of these genes was more effective at blocking cell cycle progression than disruption of the individual genes. Thus, miR-16 coordinately regulates targets that may act in concert to control cell cycle progression.


systematic_name: M2306
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HepG2 cells (hepatocellular carcinoma, HCC) upon expression of HNF4A [GeneID=3172] and down-regulated upon knockdown of HNF4A [GeneID=3172] in these cells by RNAi.

description_full:
  Cholesterol homeostasis is maintained by coordinate regulation of cholesterol synthesis and its conversion to bile acids in the liver. The excretion of cholesterol from liver and intestine is regulated by ATP-binding cassette half-transporters ABCG5 and ABCG8. The genes for these two proteins are closely linked and divergently transcribed from a common intergenic promoter region. Here, we identified a binding site for hepatocyte nuclear factor 4alpha (HNF4alpha) in the ABCG5/ABCG8 intergenic promoter, through which HNF4alpha strongly activated the expression of a reporter gene in both directions. The HNF4alpha-responsive element is flanked by two conserved GATA boxes that were also required for stimulation by HNF4alpha. GATA4 and GATA6 bind to the GATA boxes, coexpression of GATA4 and HNF4alpha leads to a striking synergistic activation of both the ABCG5 and the ABCG8 promoters, and binding sites for HNF4alpha and GATA were essential for maximal synergism. We also show that HNF4alpha, GATA4, and GATA6 colocalize in the nuclei of HepG2 cells and that a physical interaction between HNF4alpha and GATA4 is critical for the synergistic response. This is the first demonstration that HNF4alpha acts synergistically with GATA factors to activate gene expression in a bidirectional fashion.


systematic_name: M2309
exact_source: Table 1S: Fold Change < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in RWPE-1 cells (prostate cancer) upon expression of constitutively active form of STAT3 [GeneID=6774].

description_full:
  The persistent activation of signal transducer and activator of transcription 3 (Stat3) is a common feature of prostate cancer. However, little is known about the Stat3 targets that may mediate prostate tumorigenesis. The introduction of an activating mutant form of Stat3 (Stat3-C) into immortalized prostate epithelial cells resulted in tumorigenesis. Stat3-C-expressing cells had decreased E-cadherin levels, increased numbers of lamellipodia and stress fibers, and enhanced migratory capacities compared to vector control-expressing cells, with a concomitant increase in the expression of integrin beta6 and its ligand, fibronectin (FN). Exogenously added FN increased cellular migration, with a concomitant loss of E-cadherin expression. The blockade of integrin alphavbeta6 in Stat3-C-expressing cells inhibited migration, increased E-cadherin levels, and reduced colony formation in soft agar. These results demonstrate the sufficiency of constitutively activated Stat3 in mediating prostate tumorigenesis and identify novel Stat3 targets that are involved in promoting cell migration and transformation.


systematic_name: M2311
exact_source: Table 1S: Fold Change > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in RWPE-1 cells (prostate cancer) upon expression of constitutively active form of STAT3 [GeneID=6774].

description_full:
  The persistent activation of signal transducer and activator of transcription 3 (Stat3) is a common feature of prostate cancer. However, little is known about the Stat3 targets that may mediate prostate tumorigenesis. The introduction of an activating mutant form of Stat3 (Stat3-C) into immortalized prostate epithelial cells resulted in tumorigenesis. Stat3-C-expressing cells had decreased E-cadherin levels, increased numbers of lamellipodia and stress fibers, and enhanced migratory capacities compared to vector control-expressing cells, with a concomitant increase in the expression of integrin beta6 and its ligand, fibronectin (FN). Exogenously added FN increased cellular migration, with a concomitant loss of E-cadherin expression. The blockade of integrin alphavbeta6 in Stat3-C-expressing cells inhibited migration, increased E-cadherin levels, and reduced colony formation in soft agar. These results demonstrate the sufficiency of constitutively activated Stat3 in mediating prostate tumorigenesis and identify novel Stat3 targets that are involved in promoting cell migration and transformation.


systematic_name: M2338
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top scoring genes whose transcripts bound TIAR1 [GeneID=7073] in extracts from RKO cells (colon cancer).

description_full:
  The RNA-binding protein TIAR (related to TIA-1 [T-cell-restricted intracellular antigen 1]) was shown to associate with subsets of mRNAs bearing U-rich sequences in their 3' untranslated regions. TIAR can function as a translational repressor, particularly in response to cytotoxic agents. Using unstressed colon cancer cells, collections of mRNAs associated with TIAR were isolated by immunoprecipitation (IP) of (TIAR-RNA) ribonucleoprotein (RNP) complexes, identified by microarray analysis, and used to elucidate a common signature motif present among TIAR target transcripts. The predicted TIAR motif was an unexpectedly cytosine-rich, 28- to 32-nucleotide-long element forming a stem and a loop of variable size with an additional side loop. The ability of TIAR to bind an RNA oligonucleotide with a representative C-rich TIAR motif sequence was verified in vitro using surface plasmon resonance. By this analysis, TIAR containing two or three RNA recognition domains (TIAR12 and TIAR123) showed low but significant binding to the C-rich sequence. In vivo, insertion of the C-rich motif into a heterologous reporter strongly suppressed its translation in cultured cells. Using this signature motif, an additional approximately 2,209 UniGene targets were identified (2.0% of the total UniGene database). A subset of specific mRNAs were validated by RNP IP analysis. Interestingly, in response to treatment with short-wavelength UV light (UVC), a stress agent causing DNA damage, each of these target mRNAs bearing C-rich motifs dissociated from TIAR. In turn, expression of the encoded proteins was elevated in a TIAR-dependent manner. In sum, we report the identification of a C-rich signature motif present in TIAR target mRNAs whose association with TIAR decreases following exposure to a stress-causing agent.


description_brief: Direct targets of PRDM5 [GeneID=11107].
systematic_name: M2339
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Gfi1 transcriptionally governs hematopoiesis, and its mutations produce neutropenia. In an effort to identify Gfi1-interacting proteins and also to generate new candidate genes causing neutropenia, we performed a yeast two-hybrid screen with Gfi1. Among other Gfi1-interacting proteins, we identified a previously uncharacterized member of the PR domain-containing family of tumor suppressors, PRDM5. PRDM5 has 16 zinc fingers, and we show that it acts as a sequence-specific, DNA binding transcription factor that targets hematopoiesis-associated protein-coding and microRNA genes, including many that are also targets of Gfi1. PRDM5 epigenetically regulates transcription similarly to Gfi1: it recruits the histone methyltransferase G9a and class I histone deacetylases to its target gene promoters and demonstrates repressor activity on synthetic reporters; on endogenous target genes, however, it functions as an activator, in addition to a repressor. Interestingly, genes that PRDM5 activates, as opposed to those it represses, are also targets of Gfi1, suggesting a competitive mechanism through which two repressors could cooperate in order to become transcriptional activators. In neutropenic patients, we identified PRDM5 protein sequence variants perturbing transcriptional function, suggesting a potentially important role in hematopoiesis.


description_brief: Proteins associated with ZNF143 [GeneID=7702] in HeLa cells, based on MudPIT analysis.
systematic_name: M2355
exact_source: Fig. 2B
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Chromatin remodeling and histone modification are essential for eukaryotic transcription regulation, but little is known about chromatin-modifying activities acting on RNA polymerase III (Pol III)-transcribed genes. The human U6 small nuclear RNA promoter, located 5' of the transcription start site, consists of a core region directing basal transcription and an activating region that recruits the transcription factors Oct-1 and Staf (ZNF143). Oct-1 activates transcription in part by helping recruit core binding factors, but nothing is known about the mechanisms of transcription activation by Staf. We show that Staf activates U6 transcription from a preassembled chromatin template in vitro and associates with several proteins linked to chromatin modification, among them chromodomain-helicase-DNA binding protein 8 (CHD8). CHD8 binds to histone H3 di- and trimethylated on lysine 4. It resides on the human U6 promoter as well as the mRNA IRF3 promoter in vivo and contributes to efficient transcription from both these promoters. Thus, Pol III transcription from type 3 promoters uses some of the same factors used for chromatin remodeling at Pol II promoters.


systematic_name: M2364
exact_source: Table 2S: up-regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HEK-293 cells (fibroblast) upon knockdown of both CTBP1 and SATB1 [GeneID=1487, 6304] by RNAi.

description_full:
  Special AT-rich binding protein 1 (SATB1) acts as a global regulator of gene expression by recruiting various corepressor or coactivator complexes, thereby establishing a unique chromatin structure at its genomic targets in a context-dependent manner. Although SATB1 acts predominantly as a repressor via recruitment of histone deacetylase 1 (HDAC1) complexes, the precise mechanism of global repression is not clear. Here we report that SATB1 and C-terminal binding protein 1 (CtBP1) form a repressor complex in vivo. The interaction occurs via the CtBP1 interaction consensus motif PVPLS within the PDZ-like domain of SATB1. The acetylation of SATB1 upon LiCl and ionomycin treatments disrupts its association with CtBP1, resulting in enhanced target gene expression. Chromatin immunoprecipitation analysis indicated that the occupancy of CtBP1 and HDAC1 is gradually decreased and the occupancy of PCAF is elevated at the SATB1 binding sites within the human interleukin-2 and mouse c-Myc promoters. Moreover, gene expression profiling studies using cells in which expression of SATB1 and CtBP1 was silenced indicated commonly targeted genes that may be coordinately repressed by the SATB1-CtBP1 complex. Collectively, these results provide a mechanistic insight into the role of SATB1-CtBP1 interaction in the repression and derepression of SATB1 target genes during Wnt signaling in T cells.


systematic_name: M2365
exact_source: Table 2S: down-regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in HEK-293 cells (fibroblast) upon knockdown of both CTBP1 and SATB1 [GeneID=1487, 6304] by RNAi.

description_full:
  Special AT-rich binding protein 1 (SATB1) acts as a global regulator of gene expression by recruiting various corepressor or coactivator complexes, thereby establishing a unique chromatin structure at its genomic targets in a context-dependent manner. Although SATB1 acts predominantly as a repressor via recruitment of histone deacetylase 1 (HDAC1) complexes, the precise mechanism of global repression is not clear. Here we report that SATB1 and C-terminal binding protein 1 (CtBP1) form a repressor complex in vivo. The interaction occurs via the CtBP1 interaction consensus motif PVPLS within the PDZ-like domain of SATB1. The acetylation of SATB1 upon LiCl and ionomycin treatments disrupts its association with CtBP1, resulting in enhanced target gene expression. Chromatin immunoprecipitation analysis indicated that the occupancy of CtBP1 and HDAC1 is gradually decreased and the occupancy of PCAF is elevated at the SATB1 binding sites within the human interleukin-2 and mouse c-Myc promoters. Moreover, gene expression profiling studies using cells in which expression of SATB1 and CtBP1 was silenced indicated commonly targeted genes that may be coordinately repressed by the SATB1-CtBP1 complex. Collectively, these results provide a mechanistic insight into the role of SATB1-CtBP1 interaction in the repression and derepression of SATB1 target genes during Wnt signaling in T cells.


systematic_name: M2366
exact_source: Table 3S: up-regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HEK-293 cells (fibroblast) upon knockdown of CTBP1 but not of SATB1 [GeneID=1487, 6304] by RNAi.

description_full:
  Special AT-rich binding protein 1 (SATB1) acts as a global regulator of gene expression by recruiting various corepressor or coactivator complexes, thereby establishing a unique chromatin structure at its genomic targets in a context-dependent manner. Although SATB1 acts predominantly as a repressor via recruitment of histone deacetylase 1 (HDAC1) complexes, the precise mechanism of global repression is not clear. Here we report that SATB1 and C-terminal binding protein 1 (CtBP1) form a repressor complex in vivo. The interaction occurs via the CtBP1 interaction consensus motif PVPLS within the PDZ-like domain of SATB1. The acetylation of SATB1 upon LiCl and ionomycin treatments disrupts its association with CtBP1, resulting in enhanced target gene expression. Chromatin immunoprecipitation analysis indicated that the occupancy of CtBP1 and HDAC1 is gradually decreased and the occupancy of PCAF is elevated at the SATB1 binding sites within the human interleukin-2 and mouse c-Myc promoters. Moreover, gene expression profiling studies using cells in which expression of SATB1 and CtBP1 was silenced indicated commonly targeted genes that may be coordinately repressed by the SATB1-CtBP1 complex. Collectively, these results provide a mechanistic insight into the role of SATB1-CtBP1 interaction in the repression and derepression of SATB1 target genes during Wnt signaling in T cells.


systematic_name: M2381
exact_source: Fig. 2A
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Transcripts stabilized by NO [PubChem=145068] identified as up-regulated by NO [PubChem=145068] in the presence of actinomycin D [PubChemiD=2019] in IMR-90 and NIH 3T3 cells (fibroblast).

description_full:
  We previously observed that nitric oxide (NO) exposure increases the stability of mRNAs encoding heme oxygenase 1 (HO-1) and TIEG-1 in human and mouse fibroblasts. Here, we have used microarrays to look broadly for changes in mRNA stability in response to NO treatment. Using human IMR-90 and mouse NIH 3T3 fibroblasts treated with actinomycin D to block de novo transcription, microarray analysis suggested that the stability of the majority of mRNAs was unaffected. Among the mRNAs that were stabilized by NO treatment, seven transcripts were found in both IMR-90 and NIH 3T3 cells (CHIC2, GADD45B, HO-1, PTGS2, RGS2, TIEG, and ID3) and were chosen for further analysis. All seven mRNAs showed at least one hit of a signature motif for the stabilizing RNA-binding protein (RBP) HuR; accordingly, ribonucleoprotein immunoprecipitation analysis revealed that all seven mRNAs associated with HuR. In keeping with a functional role of HuR in the response to NO, a measurable fraction of HuR increased in the cytoplasm following NO treatment. However, among the seven transcripts, only HO-1 mRNA showed a robust increase in the level of its association with HuR following NO treatment. In turn, HO-1 mRNA and protein levels were significantly reduced when HuR levels were silenced in IMR-90 cells, and they were elevated when HuR was overexpressed. In sum, our results indicate that NO stabilizes mRNA subsets in fibroblasts, identify HuR as an RBP implicated in the NO response, reveal that HuR alone is insufficient for stabilizing several mRNAs by NO, and show that HO-1 induction by NO is regulated by HuR.


description_brief: Genes down-regulated in testis tissue expressing hypomorphic allele of THOC1 [GeneID=9984].
systematic_name: M2391
exact_source: Table 1S: logFC < 0
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Accumulating evidence suggests that regulation of RNA processing through an RNP-driven mechanism is important for coordinated gene expression. This hypothesis predicts that defects in RNP biogenesis will adversely affect the elaboration of specific gene expression programs. To explore the role of RNP biogenesis on mammalian development, we have characterized the phenotype of mice hypomorphic for Thoc1. Thoc1 encodes an essential component of the evolutionarily conserved TREX complex. TREX accompanies the elongating RNA polymerase II and facilitates RNP assembly and recruitment of RNA processing factors. Hypomorphic Thoc1 mice are viable despite significantly reduced Thoc1 expression in the tissues examined. While most tissues of Thoc1-deficient mice appear to develop and function normally, gametogenesis is severely compromised. Male infertility is associated with a loss in spermatocyte viability and abnormal endocrine signaling. We suggest that loss of spermatocyte viability is a consequence of defects in the expression of genes required for normal differentiation of cell types within the testes. A number of the genes affected appear to be direct targets for regulation by Thoc1. These findings support the notion that Thoc1-mediated RNP assembly contributes to the coordinated expression of genes necessary for normal differentiation and development in vivo.


systematic_name: M2408
exact_source: Table 1S: Probeset average sheet: Both 611- 15h and 60h regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes regulated in MCF7 cells (breast cancer) by expression of the truncated (611-CTF) form of ERBB2 [GeneID=2064] at both 15 h and 60 h time points.

description_full:
  HER2 is a tyrosine kinase receptor causally involved in cancer. A subgroup of breast cancer patients with particularly poor clinical outcomes expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTFs). However, since the CTFs lack the extracellular domain that drives dimerization and subsequent activation of full-length HER2, they are in principle expected to be inactive. Here we show that at low expression levels one of these fragments, 611-CTF, activated multiple signaling pathways because of its unanticipated ability to constitutively homodimerize. A transcriptomic analysis revealed that 611-CTF specifically controlled the expression of genes that we found to be correlated with poor prognosis in breast cancer. Among the 611-CTF-regulated genes were several that have previously been linked to metastasis, including those for MET, EPHA2, matrix metalloproteinase 1, interleukin 11, angiopoietin-like 4, and different integrins. It is thought that transgenic mice overexpressing HER2 in the mammary glands develop tumors only after acquisition of activating mutations in the transgene. In contrast, we show that expression of 611-CTF led to development of aggressive and invasive mammary tumors without the need for mutations. These results demonstrate that 611-CTF is a potent oncogene capable of promoting mammary tumor progression and metastasis.


systematic_name: M2410
exact_source: Table 1S: Probeset average sheet: Both 611-60h and HER2-60h regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes regulated in MCF7 cells (breast cancer) by expression of the full-length and truncated (611-CTF) forms of ERBB2 [GeneID=2064] at 60 h time point.

description_full:
  HER2 is a tyrosine kinase receptor causally involved in cancer. A subgroup of breast cancer patients with particularly poor clinical outcomes expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTFs). However, since the CTFs lack the extracellular domain that drives dimerization and subsequent activation of full-length HER2, they are in principle expected to be inactive. Here we show that at low expression levels one of these fragments, 611-CTF, activated multiple signaling pathways because of its unanticipated ability to constitutively homodimerize. A transcriptomic analysis revealed that 611-CTF specifically controlled the expression of genes that we found to be correlated with poor prognosis in breast cancer. Among the 611-CTF-regulated genes were several that have previously been linked to metastasis, including those for MET, EPHA2, matrix metalloproteinase 1, interleukin 11, angiopoietin-like 4, and different integrins. It is thought that transgenic mice overexpressing HER2 in the mammary glands develop tumors only after acquisition of activating mutations in the transgene. In contrast, we show that expression of 611-CTF led to development of aggressive and invasive mammary tumors without the need for mutations. These results demonstrate that 611-CTF is a potent oncogene capable of promoting mammary tumor progression and metastasis.


systematic_name: M2411
exact_source: Table 1S: Probeset average sheet: Only 611-15h regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes regulated in MCF7 cells (breast cancer) by expression of the truncated (611-CTF) form of ERBB2 [GeneID=2064] at 15 h time point.

description_full:
  HER2 is a tyrosine kinase receptor causally involved in cancer. A subgroup of breast cancer patients with particularly poor clinical outcomes expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTFs). However, since the CTFs lack the extracellular domain that drives dimerization and subsequent activation of full-length HER2, they are in principle expected to be inactive. Here we show that at low expression levels one of these fragments, 611-CTF, activated multiple signaling pathways because of its unanticipated ability to constitutively homodimerize. A transcriptomic analysis revealed that 611-CTF specifically controlled the expression of genes that we found to be correlated with poor prognosis in breast cancer. Among the 611-CTF-regulated genes were several that have previously been linked to metastasis, including those for MET, EPHA2, matrix metalloproteinase 1, interleukin 11, angiopoietin-like 4, and different integrins. It is thought that transgenic mice overexpressing HER2 in the mammary glands develop tumors only after acquisition of activating mutations in the transgene. In contrast, we show that expression of 611-CTF led to development of aggressive and invasive mammary tumors without the need for mutations. These results demonstrate that 611-CTF is a potent oncogene capable of promoting mammary tumor progression and metastasis.


systematic_name: M2412
exact_source: Table 1S: Probeset average sheet: Only HER2-60h regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes regulated in MCF7 cells (breast cancer) by expression of the full-length form of ERBB2 [GeneID=2064] at 60 h time point.

description_full:
[cell repeats an earlier one in this file: 1380 characters]


description_brief: Genes down-regulated in neonatal cardiac myocytes upon knockdown of BCL3 [GeneID=602] by RNAi.
systematic_name: M2425
exact_source: Table 3S: Fold change < 1
source_species_code: RN
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Estrogen-related receptors (ERRs) play critical roles in regulation of cellular energy metabolism in response to inducible coactivators such as peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha). A yeast two-hybrid screen led to the identification of the cytokine-stimulated transcriptional regulator, Bcl3, as an ERRalpha coactivator. Bcl3 was shown to synergize with PGC-1alpha to coactivate ERRalpha. Chromatin immunoprecipitation studies demonstrated that ERRalpha, PGC-1alpha, and Bcl3 form a complex on an ERRalpha-responsive element within the pyruvate dehydrogenase kinase 4 gene promoter in cardiac myocytes. Mapping studies demonstrated that Bc13 interacts with PGC-1alpha and ERRalpha, allowing for interaction with both proteins. Transcriptional profiling demonstrated that Bcl3 activates genes involved in diverse pathways including a subset involved in cellular energy metabolism known to be regulated by PGC-1alpha, ERRalpha, and a second nuclear receptor, PPARalpha. Consistent with the gene expression profiling results, Bcl3 was shown to synergistically coactivate PPARalpha with PGC-1alpha in a manner similar to ERRalpha. We propose that the cooperativity between Bcl3 and PGC-1alpha may serve as a point of convergence on nuclear receptor targets to direct programs orchestrating inflammatory and energy metabolism responses in heart and other tissues.


systematic_name: M2426
exact_source: Fig. 2D
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes translationally up-regulated in HUVEC cells (endothelium) grown on FN1 [GeneID=2335] compared to those grown on laminin 1.

description_full:
  Integrin signaling promotes, through p21-activated kinase, phosphorylation and inactivation of the tumor suppressor merlin, thus removing a block to mitogenesis in normal cells. However, the biochemical function of merlin and the effector pathways critical for the pathogenesis of malignant mesothelioma and other NF2-related malignancies are not known. We report that integrin-specific signaling promotes activation of mTORC1 and cap-dependent mRNA translation. Depletion of merlin rescues mTORC1 signaling in cells deprived of anchorage to a permissive extracellular matrix, suggesting that integrin signaling controls mTORC1 through inactivation of merlin. This signaling pathway controls translation of the cyclin D1 mRNA and, thereby, cell cycle progression. In addition, it promotes cell survival. Analysis of a panel of malignant mesothelioma cell lines reveals a strong correlation between loss of merlin and activation of mTORC1. Merlin-negative lines are sensitive to the growth-inhibitory effect of rapamycin, and the expression of recombinant merlin renders them partially resistant to rapamycin. Conversely, depletion of merlin restores rapamycin sensitivity in merlin-positive lines. These results indicate that integrin-mediated adhesion promotes mTORC1 signaling through the inactivation of merlin. Furthermore, they reveal that merlin-negative mesotheliomas display unregulated mTORC1 signaling and are sensitive to rapamycin, thus providing a preclinical rationale for prospective, biomarker-driven clinical studies of mTORC1 inhibitors in these tumors.


systematic_name: M2440
exact_source: Table 2S: Exression=Up
source_species_code: HS
GEO_id: GSE14787
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated during neuronal differentiation of SH-SY5Y cells (neuroblastoma) in response to stimulation by tretinoin (all-trans retinoic acid, ATRA) [PubChem=444795] and BDNF [GeneID=627].

description_full:
  MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression at the posttranscriptional level. Research on miRNAs has highlighted their importance in neural development, but the specific functions of neurally enriched miRNAs remain poorly understood. We report here the expression profile of miRNAs during neuronal differentiation in the human neuroblastoma cell line SH-SY5Y. Six miRNAs were significantly upregulated during differentiation induced by all-trans-retinoic acid and brain-derived neurotrophic factor. We demonstrated that the ectopic expression of either miR-124a or miR-125b increases the percentage of differentiated SH-SY5Y cells with neurite outgrowth. Subsequently, we focused our functional analysis on miR-125b and demonstrated the important role of this miRNA in both the spontaneous and induced differentiations of SH-SH5Y cells. miR-125b is also upregulated during the differentiation of human neural progenitor ReNcell VM cells, and miR-125b ectopic expression significantly promotes the neurite outgrowth of these cells. To identify the targets of miR-125b regulation, we profiled the global changes in gene expression following miR-125b ectopic expression in SH-SY5Y cells. miR-125b represses 164 genes that contain the seed match sequence of the miRNA and/or that are predicted to be direct targets of miR-125b by conventional methods. Pathway analysis suggests that a subset of miR-125b-repressed targets antagonizes neuronal genes in several neurogenic pathways, thereby mediating the positive effect of miR-125b on neuronal differentiation. We have further validated the binding of miR-125b to the miRNA response elements of 10 selected mRNA targets. Together, we report here for the first time the important role of miR-125b in human neuronal differentiation.


systematic_name: M2470
exact_source: Fig. 1A
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes consistently and robustly repressed by estradiol [PubChem=5757] in MCF7 cells (breast cancer); this reperession was prevented by fulvestrant [PubChem=3478439].

description_full:
  Activation of estrogen receptor alpha (ERalpha) results in both induction and repression of gene transcription; while mechanistic details of estrogen induction are well described, details of repression remain largely unknown. We characterized several ERalpha-repressed targets and examined in detail the mechanism for estrogen repression of Reprimo (RPRM), a cell cycle inhibitor. Estrogen repression of RPRM is rapid and robust and requires a tripartite interaction between ERalpha, histone deacetylase 7 (HDAC7), and FoxA1. HDAC7 is the critical HDAC needed for repression of RPRM; it can bind to ERalpha and represses ERalpha's transcriptional activity--this repression does not require HDAC7's deacetylase activity. We further show that the chromatin pioneer factor FoxA1, well known for its role in estrogen induction of genes, is recruited to the RPRM promoter, is necessary for repression of RPRM, and interacts with HDAC7. Like other FoxA1 recruitment sites, the RPRM promoter is characterized by H3K4me1/me2. Estrogen treatment causes decreases in H3K4me1/me2 and release of RNA polymerase II (Pol II) from the RPRM proximal promoter. Overall, these data implicate a novel role for HDAC7 and FoxA1 in estrogen repression of RPRM, a mechanism which could potentially be generalized to many more estrogen-repressed genes and hence be important in both normal physiology and pathological processes.


systematic_name: M2471
exact_source: Table 1
source_species_code: HS
GEO_id: GSE16924
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in both AGS and HGC-27 cells (gastric cancer) by BHLHA15 [GeneID=168620] transfection.

description_full:
  Little is known about how differentiating cells reorganize their cellular structure to perform specialized physiological functions. MIST1, an evolutionarily conserved transcription factor, is required for the formation of large, specialized secretory vesicles in gastric zymogenic (chief) cells (ZCs) as they differentiate from their mucous neck cell progenitors. Here, we show that MIST1 binds to highly conserved CATATG E-boxes to directly activate transcription of 6 genes, including those encoding the small GTPases RAB26 and RAB3D. We next show that RAB26 and RAB3D expression is significantly downregulated in Mist1(-)(/)(-) ZCs, suggesting that MIST1 establishes large secretory granules by inducing RAB transcription. To test this hypothesis, we transfected human gastric cancer cell lines stably expressing MIST1 with red fluorescent protein (RFP)-tagged pepsinogen C, a key secretory product of ZCs. Those cells upregulate expression of RAB26 and RAB3D to form large secretory granules, whereas control, non-MIST1-expressing cells do not. Moreover, granule formation in MIST1-expressing cells requires RAB activity because treatment with a RAB prenylation inhibitor and transfection of dominant negative RAB26 abrogate granule formation. Together, our data establish the molecular process by which a transcription factor can directly induce fundamental cellular architecture changes by increasing transcription of specific cellular effectors that act to organize a unique subcellular compartment.


systematic_name: M2474
exact_source: Table 2: Genes upregulated in the repeatedstimulationmodel
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in BEAS-2B cells (bronchial epithelium) stimulated with IL13 [GeneID=3596] on days 1 to 3 and then rested for the next 3 days (repeated-stimulation or memory model)

description_full:
  Our objective was to establish an experimental model of a self-sustained and bistable extracellular signal-regulated kinase 1/2 (ERK1/2) signaling process. A single stimulation of cells with cytokines causes rapid ERK1/2 activation, which returns to baseline in 4 h. Repeated stimulation leads to sustained activation of ERK1/2 but not Jun N-terminal protein kinase (JNK), p38, or STAT6. The ERK1/2 activation lasts for 3 to 7 days and depends upon a positive-feedback mechanism involving Sprouty 2. Overexpression of Sprouty 2 induces, and its genetic deletion abrogates, ERK1/2 bistability. Sprouty 2 directly activates Fyn kinase, which then induces ERK1/2 activation. A genome-wide microarray analysis shows that the bistable phospho-ERK1/2 (pERK1/2) does not induce a high level of gene transcription. This is due to its nuclear exclusion and compartmentalization to Rab5+ endosomes. Cells with sustained endosomal pERK1/2 manifest resistance against growth factor withdrawal-induced cell death. They are primed for heightened cytokine production. Epithelial cells from cases of human asthma and from a mouse model of chronic asthma manifest increased pERK1/2, which is associated with Rab5+ endosomes. The increase in pERK1/2 was associated with a simultaneous increase in Sprouty 2 expression in these tissues. Thus, we have developed a cellular model of sustained ERK1/2 activation, which may provide a mechanistic understanding of self-sustained biological processes in chronic illnesses such as asthma.


systematic_name: M2475
exact_source: Genes downregulated in therepeated-stimulation model
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in BEAS-2B cells (bronchial epithelium) stimulated with IL13 [GeneID=3596] on days 1 to 3 and then rested for the next 3 days (repeated-stimulation or memory model)

description_full:
  Our objective was to establish an experimental model of a self-sustained and bistable extracellular signal-regulated kinase 1/2 (ERK1/2) signaling process. A single stimulation of cells with cytokines causes rapid ERK1/2 activation, which returns to baseline in 4 h. Repeated stimulation leads to sustained activation of ERK1/2 but not Jun N-terminal protein kinase (JNK), p38, or STAT6. The ERK1/2 activation lasts for 3 to 7 days and depends upon a positive-feedback mechanism involving Sprouty 2. Overexpression of Sprouty 2 induces, and its genetic deletion abrogates, ERK1/2 bistability. Sprouty 2 directly activates Fyn kinase, which then induces ERK1/2 activation. A genome-wide microarray analysis shows that the bistable phospho-ERK1/2 (pERK1/2) does not induce a high level of gene transcription. This is due to its nuclear exclusion and compartmentalization to Rab5+ endosomes. Cells with sustained endosomal pERK1/2 manifest resistance against growth factor withdrawal-induced cell death. They are primed for heightened cytokine production. Epithelial cells from cases of human asthma and from a mouse model of chronic asthma manifest increased pERK1/2, which is associated with Rab5+ endosomes. The increase in pERK1/2 was associated with a simultaneous increase in Sprouty 2 expression in these tissues. Thus, we have developed a cellular model of sustained ERK1/2 activation, which may provide a mechanistic understanding of self-sustained biological processes in chronic illnesses such as asthma.


description_brief: Proteins identified by mass spectrometry in complexes containing ALKBH8 [GeneID=91801].
systematic_name: M2478
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  tRNA nucleosides are extensively modified to ensure their proper function in translation. However, many of the enzymes responsible for tRNA modifications in mammals await identification. Here, we show that human AlkB homolog 8 (ABH8) catalyzes tRNA methylation to generate 5-methylcarboxymethyl uridine (mcm(5)U) at the wobble position of certain tRNAs, a critical anticodon loop modification linked to DNA damage survival. We find that ABH8 interacts specifically with tRNAs containing mcm(5)U and that purified ABH8 complexes methylate RNA in vitro. Significantly, ABH8 depletion in human cells reduces endogenous levels of mcm(5)U in RNA and increases cellular sensitivity to DNA-damaging agents. Moreover, DNA-damaging agents induce ABH8 expression in an ATM-dependent manner. These results expand the role of mammalian AlkB proteins beyond that of direct DNA repair and support a regulatory mechanism in the DNA damage response pathway involving modulation of tRNA modification.


systematic_name: M2487
exact_source: Table 3S: sheet: Upregulated
source_species_code: HS
GEO_id: GSE20753
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HeLa cells (cervical carcinoma) upon knockdown of PHF8 [GeneID=23133] by RNAi.

description_full:
  Mutations in PHF8 are associated with X-linked mental retardation and cleft lip/cleft palate. PHF8 contains a plant homeodomain (PHD) in its N terminus and is a member of a family of JmjC domain-containing proteins. While PHDs can act as methyl lysine recognition motifs, JmjC domains can catalyze lysine demethylation. Here, we show that PHF8 is a histone demethylase that removes repressive histone H3 dimethyl lysine 9 marks. Our biochemical analysis revealed specific association of the PHF8 PHD with histone H3 trimethylated at lysine 4 (H3K4me3). Chromatin immunoprecipitation followed by high-throughput sequencing indicated that PHF8 is enriched at the transcription start sites of many active or poised genes, mirroring the presence of RNA polymerase II (RNAPII) and of H3K4me3-bearing nucleosomes. We show that PHF8 can act as a transcriptional coactivator and that its activation function largely depends on binding of the PHD to H3K4me3. Furthermore, we present evidence for direct interaction of PHF8 with the C-terminal domain of RNAPII. Importantly, a PHF8 disease mutant was defective in demethylation and in coactivation. This is the first demonstration of a chromatin-modifying enzyme that is globally recruited to promoters through its association with H3K4me3 and RNAPII.


systematic_name: M2493
exact_source: Table 4S
source_species_code: HS
GEO_id: GSE16908
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in primary LEC cells (lymphatic endothelum) upon overexpression of MIR31 [GeneID=407035].

description_full:
  The lymphatic vascular system maintains tissue fluid homeostasis, helps mediate afferent immune responses, and promotes cancer metastasis. To address the role microRNAs (miRNAs) play in the development and function of the lymphatic vascular system, we defined the in vitro miRNA expression profiles of primary human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BVECs) and identified four BVEC signature and two LEC signature miRNAs. Their vascular lineage-specific expression patterns were confirmed in vivo by quantitative real-time PCR and in situ hybridization. Functional characterization of the BVEC signature miRNA miR-31 identified a novel BVEC-specific posttranscriptional regulatory mechanism that inhibits the expression of lymphatic lineage-specific transcripts in vitro. We demonstrate that suppression of lymphatic differentiation is partially mediated via direct repression of PROX1, a transcription factor that functions as a master regulator of lymphatic lineage-specific differentiation. Finally, in vivo studies of Xenopus and zebrafish demonstrated that gain of miR-31 function impaired venous sprouting and lymphatic vascular development, thus highlighting the importance of miR-31 as a negative regulator of lymphatic development. Collectively, our findings identify miR-31 is a potent regulator of vascular lineage-specific differentiation and development in vertebrates.


systematic_name: M2498
exact_source: Table 1S: Fold changes < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in Calu-6 cells (lung cancer) at 1 h time point after TNF [GeneID=7124] treatment.

description_full:
  p38 mitogen-activated protein kinase (MAPK) is rapidly activated by stresses and is believed to play an important role in the stress response. While Chk1 is known to mediate G(2) DNA damage checkpoint control, p38 was also reported to have an essential function in this checkpoint control. Here, we have investigated further the roles of p38 and Chk1 in the G(2) DNA damage checkpoint in cancer cells. We find that although p38 activation is strongly induced by DNA damage, its activity is not required for the G(2) DNA damage checkpoint. In contrast, Chk1 kinase is responsible for the execution of G(2) DNA damage checkpoint control in p53-deficient cells. The inhibition of p38 activity has no effect on Chk1 activation and gamma-H2AX expression. Global gene expression profiling of cancer cells in response to tumor necrosis factor alpha (TNF-alpha) revealed that p38 plays a strong prosurvival role through the coordinated downregulation of proapoptotic genes and upregulation of prosurvival genes. We show that the inhibition of p38 activity during G(2) DNA damage checkpoint arrest triggers apoptosis in a p53-independent manner with a concurrent decrease in the level of Bcl2 family proteins. Our results suggest that although p38 MAPK is not required for the G(2) DNA damage checkpoint function, it plays an important prosurvival role during the G(2) DNA damage checkpoint response through the upregulation of the Bcl2 family proteins.


description_brief: Transcripts bound by CELF1 [GeneID=10658] in HeLa cells (cervical carcinoma).
systematic_name: M2505
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  CUG-repeat binding protein 1 (CUGBP1) mediates selective mRNA decay by binding to GU-rich elements (GREs) containing the sequence UGUUUGUUUGU found in the 3' untranslated region (UTR) of short-lived transcripts. We used an anti-CUGBP1 antibody to immunoprecipitate CUGBP1 from HeLa cytoplasmic extracts and analyzed the associated transcripts using oligonucleotide microarrays. We identified 613 putative mRNA targets of CUGBP1 and found that the UGUUUGUUUGU GRE sequence and a GU-repeat sequence were both highly enriched in the 3' UTRs of these targets. We showed that CUGBP1 bound specifically to the GU-repeat sequence and that insertion of this sequence into the 3' UTR of a beta-globin reporter transcript conferred instability to the transcript. Based on these results, we redefined the GRE to include this GU-repeat sequence. Our results suggest that CUGBP1 coordinately regulates the mRNA decay of a network of transcripts involved in cell growth, cell motility, and apoptosis.


description_brief: Genes representing Th1 / cytotoxic module in sputum during asthma exacerbations.
systematic_name: M2527
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE19903
contributor: Antony Bosco
contrib_organization: Telethon Kids Institute
description_full:
  Asthma exacerbations are associated with subsequent deficits in lung function. Here, we tested the hypothesis that a specific pattern of inflammatory responses during acute exacerbations may be associated with chronic airway obstruction. Gene coexpression networks were characterized in induced sputum obtained during an acute exacerbation, from asthmatic children with or without chronic airflow limitation. The data showed that activation of Th1-like/cytotoxic and interferon signaling pathways during acute exacerbations was decreased in asthmatic children with deficits in baseline lung function. These associations were independent of the identification of picornaviruses in nasal secretions or the use of medications at the time of the exacerbation. Th2-related pathways were also detected in the responses, but variations in these pathways were not related to chronic airways obstruction. Our findings show that decreased activation of Th1-like/cytotoxic and interferon pathways is a hallmark of acute exacerbation responses in asthmatic children with evidence of chronic airways obstruction.


systematic_name: M2538
exact_source: Table 1BS
source_species_code: HS
GEO_id: GSE19052
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes indentified by RNAi screen as regulating infection of THP-1 cells (macrophage) with Mycobacterium tuberculosis.

description_full:
  We performed a genome-wide siRNA screen to identify host factors that regulated pathogen load in human macrophages infected with a virulent strain of Mycobacterium tuberculosis. Iterative rounds of confirmation, followed by validation, identified 275 such molecules that were all found to functionally associate with each other through a dense network of interactions. This network then yielded to a molecular description of the host cell functional modules that were both engaged and perturbed by the pathogen. Importantly, a subscreen against a panel of field isolates revealed that the molecular composition of the host interface varied with both genotype and the phenotypic properties of the pathogen. An analysis of these differences, however, permitted identification of those host factors that were invariantly involved, regardless of the diversification in adaptive mechanisms employed by the pathogen. Interestingly, these factors were found to predominantly function through the regulation of autophagy.


systematic_name: M2539
exact_source: Table 9S
source_species_code: HS
GEO_id: GSE19052
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes defining the Mycobacterium tuberculosis strain-independent regulatory axis of the host macrophage cells.

description_full:
  We performed a genome-wide siRNA screen to identify host factors that regulated pathogen load in human macrophages infected with a virulent strain of Mycobacterium tuberculosis. Iterative rounds of confirmation, followed by validation, identified 275 such molecules that were all found to functionally associate with each other through a dense network of interactions. This network then yielded to a molecular description of the host cell functional modules that were both engaged and perturbed by the pathogen. Importantly, a subscreen against a panel of field isolates revealed that the molecular composition of the host interface varied with both genotype and the phenotypic properties of the pathogen. An analysis of these differences, however, permitted identification of those host factors that were invariantly involved, regardless of the diversification in adaptive mechanisms employed by the pathogen. Interestingly, these factors were found to predominantly function through the regulation of autophagy.


systematic_name: M2542
exact_source: Table 2S: Mean FC > 0 (red)
source_species_code: HS
GEO_id: GSE24006
contributor: Andrew Gentles
contrib_organization: Stanford University
description_brief:
  Genes up-regulated in LSC (leukemic stem) cells compared to LPC (leukemia progenitor) cells from AML (acute myeloid leukemia) tumor samples.

description_full:
  In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immunodeficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemic stem cells (LSCs). This model has significant implications for the development of novel therapies, but its clinical relevance has yet to be determined.


systematic_name: M2543
exact_source: Table 2S: Mean FC < 0 (green)
source_species_code: HS
GEO_id: GSE24006
contributor: Andrew Gentles
contrib_organization: Stanford University
description_brief:
  Genes down-regulated in LSC (leukemic stem) cells compared to LPC (leukemia progenitor) cells from AML (acute myeloid leukemia) tumor samples.

description_full:
  In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immunodeficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemic stem cells (LSCs). This model has significant implications for the development of novel therapies, but its clinical relevance has yet to be determined.


systematic_name: M2544
exact_source: Table 1S: Fold (PN/PT) < 1
source_species_code: HS
GEO_id: GSE14520
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in liver samples containing tumor thrombi in the major branches of the portal vein at surgery (PT) compared to those from metastasis-free HCC patients (PN) at the time of surgery and at follow-up.

description_full:
  Metastasis-related recurrence often occurs in hepatocellular carcinoma (HCC) patients who receive curative therapies. At present, it is challenging to identify patients with high risk of recurrence, which would warrant additional therapies. In this study, we sought to analyze a recently developed metastasis-related gene signature for its utility in predicting HCC survival, using 2 independent cohorts consisting of a total of 386 patients who received radical resection. Cohort 1 contained 247 predominantly HBV-positive cases analyzed with an Affymetrix platform, whereas cohort 2 contained 139 cases with mixed etiology analyzed with the NCI Oligo Set microarray platform. We employed a survival risk prediction algorithm with training, test, and independent cross-validation strategies and found that the gene signature is predictive of overall and disease-free survival. Importantly, risk was significantly predicted independently of clinical characteristics and microarray platform. In addition, survival prediction was successful in patients with early disease, such as small (<5 cm in diameter) and solitary tumors, and the signature predicted particularly well for early recurrence risk (<2 years), especially when combined with serum alpha fetoprotein or tumor staging. In conclusion, we have shown in 2 independent cohorts with mixed etiologies and ethnicity that the metastasis gene signature is a useful tool to predict HCC outcome, suggesting the general utility of this classifier. We recommend the use of this classifier as a molecular diagnostic test to assess the risk that an HCC patient will develop tumor relapse within 2 years after surgical resection, particularly for those with early-stage tumors and solitary presentation.


systematic_name: M2545
exact_source: Table 1S: Fold (PN/PT) > 1
source_species_code: HS
GEO_id: GSE14520
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in liver samples containing tumor thrombi in the major branches of the portal vein at surgery (PT) compared to those from metastasis-free HCC patients (PN) at the time of surgery and at follow-up.

description_full:
  Metastasis-related recurrence often occurs in hepatocellular carcinoma (HCC) patients who receive curative therapies. At present, it is challenging to identify patients with high risk of recurrence, which would warrant additional therapies. In this study, we sought to analyze a recently developed metastasis-related gene signature for its utility in predicting HCC survival, using 2 independent cohorts consisting of a total of 386 patients who received radical resection. Cohort 1 contained 247 predominantly HBV-positive cases analyzed with an Affymetrix platform, whereas cohort 2 contained 139 cases with mixed etiology analyzed with the NCI Oligo Set microarray platform. We employed a survival risk prediction algorithm with training, test, and independent cross-validation strategies and found that the gene signature is predictive of overall and disease-free survival. Importantly, risk was significantly predicted independently of clinical characteristics and microarray platform. In addition, survival prediction was successful in patients with early disease, such as small (<5 cm in diameter) and solitary tumors, and the signature predicted particularly well for early recurrence risk (<2 years), especially when combined with serum alpha fetoprotein or tumor staging. In conclusion, we have shown in 2 independent cohorts with mixed etiologies and ethnicity that the metastasis gene signature is a useful tool to predict HCC outcome, suggesting the general utility of this classifier. We recommend the use of this classifier as a molecular diagnostic test to assess the risk that an HCC patient will develop tumor relapse within 2 years after surgical resection, particularly for those with early-stage tumors and solitary presentation.


systematic_name: M2547
exact_source: Fig. 5S: R/S ratio > 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing prednisolone [PubChem=5755] resistant and sensitive B-lineage ALL; here - genes up-regulated in the drug resistant samples.

description_full:
  Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown.


systematic_name: M2548
exact_source: Fig. 5S: R/S ratio < 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing prednisolone [PubChem=5755] resistant and sensitive B-lineage ALL; here - genes down-regulated in the drug resistant samples.

description_full:
  Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown.


systematic_name: M2550
exact_source: Fig. 6S: R/S ratio > 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing vincristine [PubChem=5978] resistant and sensitive B-lineage ALL; here - genes up-regulated in the drug resistant samples.

description_full:
  Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown.


systematic_name: M2552
exact_source: Fig. 6S: R/S ratio < 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing vincristine [PubChem=5978] resistant and sensitive B-lineage ALL; here - genes down-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2554
exact_source: Fig. 7S: R/S ratio < 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing asparaginase resistant and sensitive B-lineage ALL; here - genes down-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2556
exact_source: Fig. 8S: R/S ratio > 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing daunorubicin [PubChem=30323] resistant and sensitive B-lineage ALL; here - genes up-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2557
exact_source: Fig. 8S: R/S ratio < 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing daunorubicin [PubChem=30323] resistant and sensitive B-lineage ALL; here - genes down-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2558
exact_source: Fig. 9S: R/S ratio > 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing prednisolone [PubChem=5755] resistant and sensitive ALL (B- and T-lineage ALL); here - genes up-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2560
exact_source: Fig. 9S: R/S ratio < 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing prednisolone [PubChem=5755] resistant and sensitive ALL (B- and T-lineage ALL); here - genes down-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2561
exact_source: Fig. 10S: R/S ratio > 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing vincristine [PubChem=5978] resistant and sensitive ALL (B- and T-lineage ALL); here - genes up-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2562
exact_source: Fig. 10S: R/S ratio < 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing vincristine [PubChem=5978] resistant and sensitive ALL (B- and T-lineage ALL); here - genes down-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2563
exact_source: Fig. 12S: R/S > 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing daunorubicin [PubChem=30323] resistant and sensitive ALL (B- and T-lineage ALL); here - genes up-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2564
exact_source: Fig. 12S: R/S < 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing daunorubicin [PubChem=30323] resistant and sensitive ALL (B- and T-lineage ALL); here - genes down-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2566
exact_source: Fig. 11S: R/S < 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing asparaginase resistant and sensitive ALL (B- and T-lineage ALL); here - genes down-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2594
exact_source: Table 1S: FDR < 0.1 & mean < 1
source_species_code: HS
GEO_id: GSE12435
contributor: Itai Pashtan
contrib_organization: Dana-Farber Cancer Institute
description_brief:
  Genes significantly (FDR < 10%) down-regulated in IMR-90 cells (fibroblast) in response to direct irradiation.

description_full:
  Background: The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is now well established. It raises concerns for the interpretation of risks arising from exposure to low doses of ionizing radiation. However, the regulatory mechanisms involved in the bystander response have not been well elucidated. To provide insight into the signaling pathways responding in bystanders, we have measured global gene expression four hours after bystander and direct alpha particle exposure of primary human lung fibroblasts. Results: Although common p53-regulated radiation response genes like CDKN1A were expressed at elevated levels in the directly exposed cultures, they showed little or no change in the bystanders. In contrast, genes regulated by NF_B, such as PTGS2 (cyclooxygenase-2), IL8 and BCL2A1, responded nearly identically in bystander and irradiated cells. This trend was substantiated by gene ontology and pathway analyses of the microarray data, which suggest that bystander cells mount a full NF_B response, but a muted or partial p53 response. In time-course analyses, quantitative real-time PCR measurements of CDKN1A showed the expected 4-hour peak of expression in irradiated but not bystander cells. In contrast, PTGS2, IL8 and BCL2A1 responded with two waves of expression in both bystander and directly irradiated cells, one peaking at half an hour and the other between four and six hours after irradiation. Conclusion: Two major transcriptional hubs that regulate the direct response to ionizing radiation are also implicated in regulation of the bystander response, but to dramatically different degrees. While activation of the p53 response pathway is minimal in bystander cells, the NF_B response is virtually identical in irradiated and bystander cells. This alteration in the balance of signaling is likely to lead to different outcomes in irradiated cells and their bystanders, perhaps leading to greater survival of bystanders and increased risk from any long-term damage they have sustained.


systematic_name: M2599
exact_source: Table 2S: FDR < 0.1
source_species_code: HS
GEO_id: GSE12435
contributor: Itai Pashtan
contrib_organization: Dana-Farber Cancer Institute
description_brief:
  Genes significantly (FDR < 10%) down-regulated in IMR-90 cells (fibroblast) in response to bystander irradiation.

description_full:
  Background: The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is now well established. It raises concerns for the interpretation of risks arising from exposure to low doses of ionizing radiation. However, the regulatory mechanisms involved in the bystander response have not been well elucidated. To provide insight into the signaling pathways responding in bystanders, we have measured global gene expression four hours after bystander and direct alpha particle exposure of primary human lung fibroblasts. Results: Although common p53-regulated radiation response genes like CDKN1A were expressed at elevated levels in the directly exposed cultures, they showed little or no change in the bystanders. In contrast, genes regulated by NF_B, such as PTGS2 (cyclooxygenase-2), IL8 and BCL2A1, responded nearly identically in bystander and irradiated cells. This trend was substantiated by gene ontology and pathway analyses of the microarray data, which suggest that bystander cells mount a full NF_B response, but a muted or partial p53 response. In time-course analyses, quantitative real-time PCR measurements of CDKN1A showed the expected 4-hour peak of expression in irradiated but not bystander cells. In contrast, PTGS2, IL8 and BCL2A1 responded with two waves of expression in both bystander and directly irradiated cells, one peaking at half an hour and the other between four and six hours after irradiation. Conclusion: Two major transcriptional hubs that regulate the direct response to ionizing radiation are also implicated in regulation of the bystander response, but to dramatically different degrees. While activation of the p53 response pathway is minimal in bystander cells, the NF_B response is virtually identical in irradiated and bystander cells. This alteration in the balance of signaling is likely to lead to different outcomes in irradiated cells and their bystanders, perhaps leading to greater survival of bystanders and increased risk from any long-term damage they have sustained.


description_brief: Genes down-regulated by second pulse of EGF [GeneID =1950] in 184A1 cells (mammary epithelium).
systematic_name: M2615
exact_source: Table 2S: Down-regulated by 2nd pulse
source_species_code: HS
GEO_id: GSE27629
contributor: Yaara Zwang
contrib_organization: Broad Institute
description_full:
  Normal cells require continuous exposure to growth factors in order to cross a restriction point and commit to cell-cycle progression. This can be replaced by two short, appropriately spaced pulses of growth factors, where the first pulse primes a process, which is completed by the second pulse, and enables restriction point crossing. Through integration of comprehensive proteomic and transcriptomic analyses of each pulse, we identified three processes that regulate restriction point crossing: (1) The first pulse induces essential metabolic enzymes and activates p53-dependent restraining processes. (2) The second pulse eliminates, via the PI3K/AKT pathway, the suppressive action of p53, as well as (3) sets an ERK-EGR1 threshold mechanism, which digitizes graded external signals into an all-or-none decision obligatory for S phase entry. Together, our findings uncover two gating mechanisms, which ensure that cells ignore fortuitous growth factors and undergo proliferation only in response to consistent mitogenic signals.


systematic_name: M2616
exact_source: Table 2S: Transiently induced, 2nd pulse only
source_species_code: HS
GEO_id: GSE27629
contributor: Yaara Zwang
contrib_organization: Broad Institute
description_brief:
  Genes transiently induced only by the second pulse of EGF [GeneID =1950] in 184A1 cells (mammary epithelium).

description_full:
  Normal cells require continuous exposure to growth factors in order to cross a restriction point and commit to cell-cycle progression. This can be replaced by two short, appropriately spaced pulses of growth factors, where the first pulse primes a process, which is completed by the second pulse, and enables restriction point crossing. Through integration of comprehensive proteomic and transcriptomic analyses of each pulse, we identified three processes that regulate restriction point crossing: (1) The first pulse induces essential metabolic enzymes and activates p53-dependent restraining processes. (2) The second pulse eliminates, via the PI3K/AKT pathway, the suppressive action of p53, as well as (3) sets an ERK-EGR1 threshold mechanism, which digitizes graded external signals into an all-or-none decision obligatory for S phase entry. Together, our findings uncover two gating mechanisms, which ensure that cells ignore fortuitous growth factors and undergo proliferation only in response to consistent mitogenic signals.


systematic_name: M2619
exact_source: Table 2S: Interval induced
source_species_code: HS
GEO_id: GSE27629
contributor: Yaara Zwang
contrib_organization: Broad Institute
description_brief:
  Genes induced in the time interval between two pulses of EGF [GeneID =1950] in 184A1 cells (mammary epithelium).

description_full:
  Normal cells require continuous exposure to growth factors in order to cross a restriction point and commit to cell-cycle progression. This can be replaced by two short, appropriately spaced pulses of growth factors, where the first pulse primes a process, which is completed by the second pulse, and enables restriction point crossing. Through integration of comprehensive proteomic and transcriptomic analyses of each pulse, we identified three processes that regulate restriction point crossing: (1) The first pulse induces essential metabolic enzymes and activates p53-dependent restraining processes. (2) The second pulse eliminates, via the PI3K/AKT pathway, the suppressive action of p53, as well as (3) sets an ERK-EGR1 threshold mechanism, which digitizes graded external signals into an all-or-none decision obligatory for S phase entry. Together, our findings uncover two gating mechanisms, which ensure that cells ignore fortuitous growth factors and undergo proliferation only in response to consistent mitogenic signals.


systematic_name: M19675
exact_source: Fig 5S: cluster 3
source_species_code: HS
GEO_id: GSE1561
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 3: selected apocrine, basal and hypoxia genes clustered together across breast cancer samples.

description_full:
[cell repeats an earlier one in this file: 1670 characters]


systematic_name: M19230
exact_source: Supplemental Table 7
source_species_code: HS
GEO_id: GSE30377
contributor: Kolja Eppert
contrib_organization: McGill University
description_brief:
  Genes up-regulated in functionally defined leukemic stem cells (LSC) from acute myeloid leukemia (AML) patients.

description_full:
  Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying stemness properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.


systematic_name: M19231
exact_source: Supplemental Table 8
source_species_code: HS
GEO_id: GSE30377
contributor: Kolja Eppert
contrib_organization: McGill University
description_brief:
  Genes up-regulated in human hematopoietic stem cell (HSC) enriched populations compared to committed progenitors and mature cells.

description_full:
  Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying stemness properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.


systematic_name: M19232
exact_source: Supplemental Table 11: FDR 0.05 Probe Set List
source_species_code: HS
GEO_id: GSE30377
contributor: Kolja Eppert
contrib_organization: McGill University
description_brief:
  Genes up-regulated in human hematopoietic lineage committed progenitor cells versus hematopoietic stem cells (HSC) and mature cells.

description_full:
  Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying stemness properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.


systematic_name: M19233
exact_source: Fig 2D
source_species_code: HS
GEO_id: GSE30377
contributor: Kolja Eppert
contrib_organization: McGill University
description_brief:
  Shared human hematopoietic stem cell (HSC) and acute myeloid leukemia (AML) stem cell (LSC) genes: HSC genes that are highly expressed in LSC versus other leukemic cells.

description_full:
[cell repeats an earlier one in this file: 1105 characters]


systematic_name: M52
exact_source: Table S1
source_species_code: HS
GEO_id: E-MTAB-3463
contributor: Roel Quintens
contrib_organization: Belgian Nuclear Research Centre
description_brief:
  Genes up-regulated in human peripheral blood mononuclear cells (PBMC)  at 8 h after exposure to 0.1 and 1.0 Gy dose of ionizing radiation.

description_full:
  Peripheral blood mononuclear cells (PBMC) were isolated using Histopaque-1077 (Sigma-Aldrich) from 10 healthy donors (5 males, 5 females, aged 23-50). Isolated cells were resuspended at a density of 106 cells/ml and allowed to equilibrate to culture conditions at 37°C in a humidified 5% CO2 atmosphere. PBMCs were then exposed to 0 (sham), 0.1 or 1.0 Gy of X-rays (250 keV - 1 mA, 1 mm Cu) at a dose rate of 0.26 Gy/min. After irradiation, cells were incubated at 37°C in a humidified 5% CO2 atmosphere for 8 h before RNA extraction. Two weeks later, the experiment was repeated using fresh PBMCs from the same donors, resulting in a total of 60 RNA samples. Total RNA (250 ng) was used for hybridization to GeneChip Human Gene 1.0 ST arrays (Affymetrix). This gene set contains genes that were up-regulated after radiation exposure (3-way ANOVA, FDR <0.05).


description_brief: Genes directly bound and regulated by TP53[GeneID=7157].
systematic_name: M61
exact_source: Table S3
source_species_code: HS
contributor: Martin Fischer
contrib_organization: Dana-Farber Cancer Institute
description_full:
  Genes identified as transcriptionally activated by p53 in at least 5 out of 20 genome-wide p53 gene expression profiles and identified as bound by p53 within 2.5kb of the TSS in at least 4 out of 15 genome-wide p53 binding profiles.


description_brief: Cell cycle genes with peak expression in G1/S check point.
systematic_name: M107
exact_source: Table S6
source_species_code: HS
contributor: Martin Fischer
contrib_organization: Dana-Farber Cancer Institute
description_full:
  Cell cycle genes with a CC Expression Score <= -2 (identified in at least 2 genome-wide cell cycle gene expression profiles with peak expression in G1/S)


description_brief: Cell cycle genes with peak expression in G2/M check point.
systematic_name: M130
exact_source: Table S6
source_species_code: HS
contributor: Martin Fischer
contrib_organization: Dana-Farber Cancer Institute
description_full:
  Cell cycle genes with a CC Expression Score >= 2 (identified in at least 2 genome-wide cell cycle gene expression profiles with peak expression in G2/M)


systematic_name: M157
exact_source: Supplemental Table 1, tab 2
source_species_code: HS
GEO_id: GSE83728
contributor: Berkley Gryder
contrib_organization: NIH
description_brief:
  Expressed genes (FPKM>1) associated with high-confidence PAX3-FOXO1 sites with enhancers in primary tumors and cell lines, restricted to those within topological domain boundaries

description_full:
  While previous studies have attempted to identify PAX3-FOXO1 target genes, these were based either on changes in gene expression or proximity to PAX3-FOXO1 in a single cell line with no consideration of expression or chromatin context. By gene expression many targets could be falsely identified which were in fact indirect, and 336 (31%) of the nearby genes previously reported to be direct targets were not expressed, while others may not be physically interacting because of barriers in 3D chromatin space. We therefore identified high-confidence PAX3-FOXO1 target genes by a series of criteria:  first, using only PAX3-FOXO1 bound to enhancers recurrent in cell lines and tumors.  Secondly, we only selected expressed genes, as PAX3-FOXO1 was not found in repressive chromatin.  Third, we excluded nearby expressed genes if they were not found within the same topologically associated domain (TAD) as the PAX3-FOXO1 bound enhancer. Fourth, we also called out the maximally expressed gene within each TAD harboring PAX3-FOXO1. This approach removed 435 nearby but not expressed genes, and 78 expressed but out of TAD bounds.  We found 1010 high-confidence targets, 678 of which were novel, and 439 were significantly reduced by shRNA knockdown of PAX3-FOXO1 for 48 hours. Novel targets include 24 oncogenes, 14 pan-cancer upregulated genes, 53 transcription factors, and 7 imprinted genes, many of which were rapidly decommissioned upon depletion of P3F (both reduced RNA-seq and H3K27ac at their enhancers.


systematic_name: M172
exact_source: Supplemental Table 1, tab 2
source_species_code: HS
GEO_id: GSE83728
contributor: Berkley Gryder
contrib_organization: NIH
description_brief:
  Expressed genes (FPKM>1) associated with super-high-confidence PAX3-FOXO1 sites with highly-recurrent enhancers in primary tumors and cell lines, restricted to those within topological domain boundaries

description_full:
  While previous studies have attempted to identify PAX3-FOXO1 target genes, these were based either on changes in gene expression or proximity to PAX3-FOXO1 in a single cell line with no consideration of expression or chromatin context. By gene expression many targets could be falsely identified which were in fact indirect, and 336 (31%) of the nearby genes previously reported to be direct targets were not expressed, while others may not be physically interacting because of barriers in 3D chromatin space. We therefore identified high-confidence PAX3-FOXO1 target genes by a series of criteria:  first, using only PAX3-FOXO1 bound to enhancers recurrent in cell lines and tumors.  Secondly, we only selected expressed genes, as PAX3-FOXO1 was not found in repressive chromatin.  Third, we excluded nearby expressed genes if they were not found within the same topologically associated domain (TAD) as the PAX3-FOXO1 bound enhancer. Fourth, we also called out the maximally expressed gene within each TAD harboring PAX3-FOXO1. This approach removed 435 nearby but not expressed genes, and 78 expressed but out of TAD bounds.  We found 1010 high-confidence targets, 678 of which were novel, and 439 were significantly reduced by shRNA knockdown of PAX3-FOXO1 for 48 hours. Novel targets include 24 oncogenes, 14 pan-cancer upregulated genes, 53 transcription factors, and 7 imprinted genes, many of which were rapidly decommissioned upon depletion of P3F (both reduced RNA-seq and H3K27ac at their enhancers.


systematic_name: M227
exact_source: Supplemental Table 1, tab 2
source_species_code: HS
GEO_id: GSE83724
contributor: Berkley Gryder
contrib_organization: NIH
description_brief:
  Expressed genes (FPKM>1) associated with high-confidence PAX3-FOXO1 sites with enhancers in primary tumors and cell lines, restricted to those within topological domain boundaries, which are downregulated by delta log2(FPKM) < -0.2

description_full:
  We identified high-confidence PAX3-FOXO1 target genes by a series of criteria:  first, using only PAX3-FOXO1 bound to enhancers recurrent in cell lines and tumors.  Secondly, we only selected expressed genes, as PAX3-FOXO1 was not found in repressive chromatin.  Third, we excluded nearby expressed genes if they were not found within the same topologically associated domain (TAD) as the PAX3-FOXO1 bound enhancer. Fourth, we also called out the maximally expressed gene within each TAD harboring PAX3-FOXO1. This approach removed 435 nearby but not expressed genes, and 78 expressed but out of TAD bounds.  We found 1010 high-confidence targets, 678 of which were novel, and 439 were significantly reduced by shRNA knockdown of PAX3-FOXO1 for 48 hours. The reduced genes are represented in this gene set, which is a subset of GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS.


description_brief: Genes overexpressed in cholangiocarcinoma class 2 associated with poor prognosis.
systematic_name: M246
exact_source: Table S1
source_species_code: HS
GEO_id: GSE26566
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_full:
  In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. Although gene expression signatures have been associated with outcome, there is no method to predict recurrence based on combined clinical, pathology, and genomic data (from tumor and cirrhotic tissue). We evaluated gene expression signatures associated with outcome in a large cohort of patients with early stage (Barcelona-Clinic Liver Cancer 0/A), single-nodule HCC and heterogeneity of signatures within tumor tissues.


description_brief: Genes that have high expression in mammary tumors of adenomyoepithelial histology.
systematic_name: M555
exact_source: File S1: Upregulated_in_Adenomyoepithelioma
source_species_code: MM
contributor: Daniel Hollern
contrib_organization: University of North Carolina
description_full:
  Human breast cancer has been characterized by extensive transcriptional heterogeneity, with dominant patterns reflected in the intrinsic subtypes. Mouse models of breast cancer also have heterogeneous transcriptomes and we noted that specific histological subtypes were associated with particular subsets. We hypothesized that unique sets of genes define each tumor histological type across mouse models of breast cancer. Using mouse models that contained both gene expression data and expert pathologist classification of tumor histology on a sample by sample basis, we predicted and validated gene expression signatures for Papillary, EMT, Microacinar and other histological subtypes. These signatures predict known histological events across murine breast cancer models and identify counterparts of mouse mammary tumor types in subtypes of human breast cancer. Importantly, the EMT, Adenomyoepithelial, and Solid signatures were predictive of clinical events in human breast cancer. In addition, a pan-cancer comparison revealed that the histological signatures were active in a variety of human cancers such as lung, oral, and esophageal squamous tumors. Finally, the differentiation status and transcriptional activity implicit within these signatures was identified. These data reveal that within tumor histology groups are unique gene expression profiles of differentiation and pathway activity that stretch well beyond the transgenic initiating events and that have clear applicability to human cancers. As a result, our work provides a predictive resource and insights into possible mechanisms that govern tumor heterogeneity.


systematic_name: M761
exact_source: Table 1S: aRG>bRG>N (190)
source_species_code: HS
GEO_id: GSE65000
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in basal radial glia (bRG) relative to apical radial glia (aRG), and up-regulated in both aRG and bRG relative to neurons.

description_full:
  Evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. In this work, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a cell polarity-based approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia-specific expression. ARHGAP11B arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase-activating protein) on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex.


systematic_name: M798
exact_source: Table 2S: bRG≥aRG>N (394)
source_species_code: HS
GEO_id: GSE65000
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in basal radial glia (bRG) relative to apical radial glia (aRG), and up-regulated in both aRG and bRG relative to neurons.

description_full:
  Evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. In this work, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a cell polarity-based approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia-specific expression. ARHGAP11B arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase-activating protein) on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex.


systematic_name: M799
exact_source: Table 2S: without ms ortholog (56)
source_species_code: HS
GEO_id: GSE65000
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Human-specific genes up-regulated in basal radial glia (bRG) relative to apical radial glia (aRG), and up-regulated in both aRG and bRG relative to neurons.

description_full:
  Evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. In this work, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a cell polarity-based approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia-specific expression. ARHGAP11B arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase-activating protein) on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex.


systematic_name: M27963
exact_source: Table 1S: module=pink & fold change < 0.667
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes from the pink module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M27964
exact_source: Table 1S: module=purple & fold change < 0.667
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes from the purple module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M27965
exact_source: Table 1S: module=brown & fold change >= 1.5
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes from the brown module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M27966
exact_source: Table 1S: module=tan & fold change < 0.667
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes from the tan module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M27967
exact_source: Table 1S: module=salmon & fold change < 0.667
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes from the salmon module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M27968
exact_source: Table 1S: module=cyan & fold change >= 1.5
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes from the cyan module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M27969
exact_source: Table 1S: module=lightgreen & fold change < 0.667
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes from the lightgreen module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M16154
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in neutrophils upon treatment with activated protein C (PROC) [GeneID=5624] of pulmonary inflammation induced by bacterial lipopolysaccharide (LPS).

description_full:
  Recombinant human activated protein C (rhAPC) is a natural anticoagulant with potentially important anti-inflammatory properties. In humans with severe sepsis, rhAPC treatment reduces mortality, but mechanisms responsible have not been well characterized. Accumulation of activated neutrophils in the lungs and other organs during severe infection contributes to sepsis-induced organ dysfunction, including acute inflammatory lung injury. Because neutrophils express an APC receptor, we hypothesized that immunomodulatory effects of rhAPC occur, in part, via modulation of neutrophil responses. To examine this issue, we performed a double-blinded, placebo-controlled study of rhAPC in a human model of endotoxin-induced pulmonary inflammation. Administration of rhAPC significantly reduced leukocyte accumulation to the airspaces, independent of pulmonary cytokine or chemokine release. Neutrophils recovered from bronchoalveolar lavage fluid of volunteers receiving rhAPC demonstrated decreased chemotaxis ex vivo. Decreased neutrophil chemotaxis following exposure to rhAPC was confirmed in vitro. No differences were detected in gene expression, kinase activation, cytokine release, cell survival, or apoptosis of neutrophils recovered in the presence or absence of rhAPC. These studies demonstrate that rhAPC reduces both endotoxin-induced accumulation of leukocytes in the airspaces and neutrophil chemotaxis. These rhAPC-induced effects on neutrophil function may represent a mechanism by which rhAPC improves survival in patients with sepsis.


systematic_name: M34031
exact_source: Fig. 1B & Supplemental Table 2.
source_species_code: HS
contributor: Orlando Musso
contrib_organization: INSERM (Institut National de la Santé et de la Recherche Médicale), France.
description_brief:
  Genes up-regulated in the periportal-type subclass of hepatocellular carcinomas. Sets created as part of a metaanalysis of nine public transcriptomic datasets merged into a metadataset including 1133 human hepatocellular carcinomas obtained after curative resection. For platform descriptions of each one of the 9 datasets, see Figure 1B in Désert et al., Hepatology (2017), 66: 1502-1518.

description_full:
  Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve and on the prediction of early (< 2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of non-proliferative HCCs, characterized by an approximate 50% beta-catenin (CTNNB1) mutation rate. To define the clinical, pathological, molecular features and the outcome of non-proliferative HCCs, we constructed an 1133-HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNAseq set. We show that non-proliferative HCCs preserve the zonation program that distributes metabolic functions along the porto-central axis in normal liver. More precisely, we identified two well-differentiated, non-proliferation subclasses, namely Periportal-type (wild-type CTNNB1) and Perivenous-type (mutant CTNNB1), which expressed negatively correlated gene networks. The new Periportal-type subclass represented 29% of all HCCs; expressed an HNF4A-driven gene network, which was down-regulated in mouse Hnf4a-KO mice; were early-stage tumors by BCLC, CLIP and TNM staging systems; had no macrovascular invasion and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an 8-gene Periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. Conclusion: Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, Periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection.


systematic_name: M34032
exact_source: Fig. 1B & Supplemental Table 2.
source_species_code: HS
contributor: Orlando Musso
contrib_organization: INSERM (Institut National de la Santé et de la Recherche Médicale), France.
description_brief:
  Genes up-regulated in the perivenous-type subclass of hepatocellular carcinomas. Sets created as part of a metaanalysis of nine public transcriptomic datasets merged into a metadataset including 1133 human hepatocellular carcinomas obtained after curative resection. For platform descriptions of each one of the 9 datasets, see Figure 1B in Désert et al., Hepatology (2017), 66: 1502-1518.

description_full:
  Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve and on the prediction of early (< 2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of non-proliferative HCCs, characterized by an approximate 50% beta-catenin (CTNNB1) mutation rate. To define the clinical, pathological, molecular features and the outcome of non-proliferative HCCs, we constructed an 1133-HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNAseq set. We show that non-proliferative HCCs preserve the zonation program that distributes metabolic functions along the porto-central axis in normal liver. More precisely, we identified two well-differentiated, non-proliferation subclasses, namely Periportal-type (wild-type CTNNB1) and Perivenous-type (mutant CTNNB1), which expressed negatively correlated gene networks. The new Periportal-type subclass represented 29% of all HCCs; expressed an HNF4A-driven gene network, which was down-regulated in mouse Hnf4a-KO mice; were early-stage tumors by BCLC, CLIP and TNM staging systems; had no macrovascular invasion and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an 8-gene Periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. Conclusion: Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, Periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection.


systematic_name: M34033
exact_source: Fig. 1B & Supplemental Table 2.
source_species_code: HS
contributor: Orlando Musso
contrib_organization: INSERM (Institut National de la Santé et de la Recherche Médicale), France.
description_brief:
  Genes up-regulated in the extracellular matrix-type subclass of hepatocellular carcinomas. Sets created as part of a metaanalysis of nine public transcriptomic datasets merged into a metadataset including 1133 human hepatocellular carcinomas obtained after curative resection. For platform descriptions of each one of the 9 datasets, see Figure 1B in Désert et al., Hepatology (2017), 66: 1502-1518.

description_full:
  Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve and on the prediction of early (< 2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of non-proliferative HCCs, characterized by an approximate 50% beta-catenin (CTNNB1) mutation rate. To define the clinical, pathological, molecular features and the outcome of non-proliferative HCCs, we constructed an 1133-HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNAseq set. We show that non-proliferative HCCs preserve the zonation program that distributes metabolic functions along the porto-central axis in normal liver. More precisely, we identified two well-differentiated, non-proliferation subclasses, namely Periportal-type (wild-type CTNNB1) and Perivenous-type (mutant CTNNB1), which expressed negatively correlated gene networks. The new Periportal-type subclass represented 29% of all HCCs; expressed an HNF4A-driven gene network, which was down-regulated in mouse Hnf4a-KO mice; were early-stage tumors by BCLC, CLIP and TNM staging systems; had no macrovascular invasion and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an 8-gene Periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. Conclusion: Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, Periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection.


systematic_name: M34034
exact_source: Fig. 1B & Supplemental Table 2.
source_species_code: HS
contributor: Orlando Musso
contrib_organization: INSERM (Institut National de la Santé et de la Recherche Médicale), France.
description_brief:
  Genes up-regulated in the stem cell-type subclass of hepatocellular carcinomas. Sets created as part of a metaanalysis of nine public transcriptomic datasets merged into a metadataset including 1133 human hepatocellular carcinomas obtained after curative resection. For platform descriptions of each one of the 9 datasets, see Figure 1B in Désert et al., Hepatology (2017), 66: 1502-1518.

description_full:
[cell repeats an earlier one in this file: 2157 characters]


description_brief: Genes Downregulated in PBSHMS (RT4 blebbishield-to-immune cell fusion)
systematic_name: M38970
source_species_code: HS
GEO_id: GSE98980
contributor: Goodwin G. Jinesh and Ashish M. Kamat
contrib_organization: UT MD Anderson Cancer Center
description_full:
  Apoptosis is a process that kills cells. However, cancer stem cells find ways to escape death after commencement of apoptosis. One such mechanism is blebbishield emergency program, in which the apoptotic cancer stem cells first undergo apoptotic body formation but then reassemble apoptotic bodies with main body (nuclei containing) of the apoptotic cells to form spherical to elongated structures called blebbishields. Blebbishields in turn are capable of blebbishield-blebbishield fusion to form transformed stem cell spheres (transformation phase) and then give rise to individual cancer cells from spheres (exit phase). Blebbishields are also capable of fusion with immune cells. The resulting hybrids are called PBSHMS cells in this study. We did microarray analysis of live RT4 cells, and hybrid PBSHMS cells. This data set is a comparison of RT4 cells, and hybrid PBSHMS cells and the gene list includes the genes that are downregulated in blebbishield-immune cells hybrids (PBSHMS). A separate set is provided for upregulated gene list too.

exact_source:
  Supplementary table-2 & Figure-3D Genes Downregulated in PBSHMS (blebbishield-to-immune cell fusion) Log2Fold change <0.6


description_brief: Genes up-regulated in transformed spheres compared to blebbishields from RT4 cells
systematic_name: M38971
source_species_code: HS
GEO_id: GSE98980
contributor: Goodwin G. Jinesh and Ashish M. Kamat
contrib_organization: UT MD Anderson Cancer Center
description_full:
  Apoptosis is a process that kills cells. However, cancer stem cells find ways to escape death after commencement of apoptosis. One such mechanism is blebbishield emergency program, in which the apoptotic cancer stem cells first undergo apoptotic body formation but then reassemble apoptotic bodies with main body (nuclei containing) of the apoptotic cells to form spherical to elongated structures called blebbishields. Blebbishields in turn are capable of blebbishield-blebbishield fusion to form transformed stem cell spheres (transformation phase) and then give rise to individual cancer cells from spheres (exit phase). We identified blebbishield emergency program in RT4 bladder cancer cells (RT4P=P stands for parental) and did microarray analysis of live RT4P cells, blebbishields and transformed spheres. This data set is a comparison of blebbishields with transformed spheres and the gene list includes the genes that are upregulated in transformed spheres. A separate set is provided for downregulated gene list too. In addition we provide separate gene lists for upregulated and downregulated gene lists for blebbishields compared to RT4 live cells.

exact_source:
  Supplementary table-1 & Figure-2B Genes Upregulated in transformed stem cell spheres Log2Fold change >1.0


description_brief: Genes Upregulated in PBSHMS (RT4 blebbishield-to-immune cell fusion)
systematic_name: M38972
source_species_code: HS
GEO_id: GSE98980
contributor: Goodwin G. Jinesh and Ashish M. Kamat
contrib_organization: UT MD Anderson Cancer Center
description_full:
  Apoptosis is a process that kills cells. However, cancer stem cells find ways to escape death after commencement of apoptosis. One such mechanism is blebbishield emergency program, in which the apoptotic cancer stem cells first undergo apoptotic body formation but then reassemble apoptotic bodies with main body (nuclei containing) of the apoptotic cells to form spherical to elongated structures called blebbishields. Blebbishields in turn are capable of blebbishield-blebbishield fusion to form transformed stem cell spheres (transformation phase) and then give rise to individual cancer cells from spheres (exit phase). Blebbishields are also capable of fusion with immune cells. The resulting hybrids are called PBSHMS cells in this study. We did microarray analysis of live RT4P cells, and hybrid PBSHMS cells. This data set is a comparison of RT4P cells, and hybrid PBSHMS cells and the gene list includes the genes that are upregulated in blebbishield-immune cells hybrids (PBSHMS). A separate set is provided for downregulated gene list too.

exact_source:
  Supplementary table-2 & Figure-3D Genes Upregulated in PBSHMS (blebbishield-to-immune cell fusion) Log2Fold change >0.6


description_brief: Genes down-regulated in blebbishields compared to control RT4 live cells
systematic_name: M38973
exact_source: Figure-2B: Genes downregulated in blebbishields Log2Fold change <1.0
source_species_code: HS
GEO_id: GSE98980
contributor: Goodwin G. Jinesh and Ashish M. Kamat
contrib_organization: UT MD Anderson Cancer Center
description_full:
  Apoptosis is a process that kills cells. However, cancer stem cells find ways to escape death after commencement of apoptosis. One such mechanism is blebbishield emergency program, in which the apoptotic cancer stem cells first undergo apoptotic body formation but then reassemble apoptotic bodies with main body (nuclei containing) of the apoptotic cells to form spherical to elongated structures called blebbishields. Blebbishields in turn are capable of blebbishield-blebbishield fusion to form transformed stem cell spheres (transformation phase) and then give rise to individual cancer cells from spheres (exit phase). We identified blebbishield emergency program in RT4 bladder cancer cells (RT4P=parental) and did microarray analysis of live RT4P cells, blebbishields and transformed spheres. This data set is a comparison of RT4P live cells with blebbishields and the gene list includes the genes that are downregulated in blebbishields. A separate set is provided for upregulated gene list too. In addition we provide separate gene lists for upregulated and downregulated gene lists for transformed spheres compared to blebbishields.


description_brief: Genes up-regulated in blebbishields compared to control RT4 live cells
systematic_name: M38974
exact_source: Figure-2B: Genes Upregulated in blebbishields Log2Fold change >1.0
source_species_code: HS
GEO_id: GSE98980
contributor: Goodwin G. Jinesh and Ashish M. Kamat
contrib_organization: UT MD Anderson Cancer Center
description_full:
  Apoptosis is a process that kills cells. However, cancer stem cells find ways to escape death after commencement of apoptosis. One such mechanism is blebbishield emergency program, in which the apoptotic cancer stem cells first undergo apoptotic body formation but then reassemble apoptotic bodies with main body (nuclei containing) of the apoptotic cells to form spherical to elongated structures called blebbishields. Blebbishields in turn are capable of blebbishield-blebbishield fusion to form transformed stem cell spheres (transformation phase) and then give rise to individual cancer cells from spheres (exit phase). We identified blebbishield emergency program in RT4 bladder cancer cells (RT4P=parental) and did microarray analysis of live RT4P cells, blebbishields and transformed spheres. This data set is a comparison of RT4P live cells with blebbishields and the gene list includes the genes that are upregulated in blebbishields. A separate set is provided for downregulated gene list too. In addition we provide separate gene lists for upregulated and downregulated gene lists for transformed spheres compared to blebbishields.


description_brief: Genes Down-regulated in transformed spheres compared to blebbishields from RT4 cells
systematic_name: M38975
source_species_code: HS
GEO_id: GSE98980
contributor: Goodwin G. Jinesh and Ashish M. Kamat
contrib_organization: UT MD Anderson Cancer Center
description_full:
  Apoptosis is a process that kills cells. However, cancer stem cells find ways to escape death after commencement of apoptosis. One such mechanism is blebbishield emergency program, in which the apoptotic cancer stem cells first undergo apoptotic body formation but then reassemble apoptotic bodies with main body (nuclei containing) of the apoptotic cells to form spherical to elongated structures called blebbishields. Blebbishields in turn are capable of blebbishield-blebbishield fusion to form transformed stem cell spheres (transformation phase) and then give rise to individual cancer cells from spheres (exit phase). We identified blebbishield emergency program in RT4 bladder cancer cells (RT4P=P stands for parental) and did microarray analysis of live RT4P cells, blebbishields and transformed spheres. This data set is a comparison of blebbishields with transformed spheres and the gene list includes the genes that are downregulated in transformed spheres. A separate set is provided for upregulated gene list too. In addition we provide separate gene lists for upregulated and downregulated gene lists for blebbishields compared to RT4 live cells.

exact_source:
  Supplementary Table-1 & Figure-2B Genes Downregulated in transformed stem cell spheres Log2Fold change <1.0


systematic_name: M38976
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Strongly upregulated genes from differential gene expression analysis of platelets from 6 Non-ICU patients with SARS-CoV-2 infection as well as 5 healthy donors.

description_full:
  Thrombotic complications in patients with COVID-19 are common and contribute to organ failure and mortality. Patients with severe COVID-19 present with hemostatic abnormalities that mimic disseminated intravascular coagulopathy associated with sepsis with the major difference being increased risk of thrombosis rather than bleeding. However, whether SARS-CoV-2 infection alters platelet function to contribute to the pathophysiology of COVID-19 remains unknown. In this study, we report altered platelet gene expression and functional responses in patients infected with SARS-CoV-2.

exact_source:
  Supplemental Table 1: Platelet differential gene expression analysis from hospitalized non-ICU COVID-19 patients. Genes with Log2(FC)>2, pAdj<0.05.


systematic_name: M38977
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Strongly downregulated genes from differential gene expression analysis of platelets from 6 Non-ICU patients with SARS-CoV-2 infection as well as 5 healthy donors.

description_full:
  Thrombotic complications in patients with COVID-19 are common and contribute to organ failure and mortality. Patients with severe COVID-19 present with hemostatic abnormalities that mimic disseminated intravascular coagulopathy associated with sepsis with the major difference being increased risk of thrombosis rather than bleeding. However, whether SARS-CoV-2 infection alters platelet function to contribute to the pathophysiology of COVID-19 remains unknown. In this study, we report altered platelet gene expression and functional responses in patients infected with SARS-CoV-2.

exact_source:
  Supplemental Table 1: Platelet differential gene expression analysis from hospitalized non-ICU COVID-19 patients. Genes with Log2(FC)<-2, pAdj<0.05.


systematic_name: M38978
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Strongly upregulated genes from differential gene expression analysis of platelets from 4 ICU patients with SARS-CoV-2 infection as well as 5 healthy donors.

description_full:
  Thrombotic complications in patients with COVID-19 are common and contribute to organ failure and mortality. Patients with severe COVID-19 present with hemostatic abnormalities that mimic disseminated intravascular coagulopathy associated with sepsis with the major difference being increased risk of thrombosis rather than bleeding. However, whether SARS-CoV-2 infection alters platelet function to contribute to the pathophysiology of COVID-19 remains unknown. In this study, we report altered platelet gene expression and functional responses in patients infected with SARS-CoV-2.

exact_source:
  Supplemental Table 2. Platelet differential gene expression analysis from ICU COVID-19 patients. Genes with Log2(FC)>2, pAdj<0.05.


systematic_name: M38979
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Strongly downregualted genes from differential gene expression analysis of platelets from 4 ICU patients with SARS-CoV-2 infection as well as 5 healthy donors.

description_full:
[cell repeats an earlier one in this file: 583 characters]

exact_source:
  Supplemental Table 2. Platelet differential gene expression analysis from ICU COVID-19 patients. Genes with Log2(FC)<-2, pAdj<0.05.


systematic_name: M38980
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Strongly upregulated genes from differential gene expression analysis of platelets from 10 combined ICU and Non-ICU COVID-19 patients and, for comparison, 5 healthy donors

description_full:
[cell repeats an earlier one in this file: 583 characters]

exact_source:
  Supplemental Table 4. Platelet differential gene expression analysis from COVID-19 patients. Genes with Log2(FC)<-2, pAdj<0.05.


systematic_name: M38981
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Strongly downregulated genes from differential gene expression analysis of platelets from 10 combined ICU and Non-ICU COVID-19 patients and, for comparison, 5 healthy donors

description_full:
[cell repeats an earlier one in this file: 583 characters]

exact_source:
  Supplemental Table 4. Platelet differential gene expression analysis from COVID-19 patients. Genes with Log2(FC)<-2, pAdj<0.05.


systematic_name: M38982
exact_source: Supplementary Table 3A, in Mebarki et al., Oncotarget (2016), 7: 39026 - 39043
source_species_code: HS
GEO_id: GSE68633
contributor: Orlando Musso
contrib_organization: INSERM (Institut National de la Santé et de la Recherche Médicale), France.
description_brief:
  Transcriptome of human HepaRG hepatocellular carcinoma liver progenitors in responses to a WNT3A-enriched microenvironment and dissection of pathways dependent on _-catenin and/or blocked by the SFRP-like Wnt inhibitor FZD8_CRD.

description_full:
  Methods: Liver progenitor cells were incubated in a WNT-enriched microenvironment for 72hrs (200 ng/ml mouse recombinant purified Wnt3A from R&D Systems). Gene pathways dependent on downstream _-catenin were studied by _-catenin knockdown with specific siRNA. Gene pathways blocked by extracellular SFRP-like Wnt inhibitors were studied by co-incubating cells with recombinant purified FZD8_CRD (300 ng/ml, from R&D Systems). Independent culture experiments performed in triplicate include untreated cells or cells incubated with scrambled siRNA or with _-catenin-specific siRNA or with FZD8_CRD, alone or in combination with Wnt3A.


systematic_name: M38993
exact_source: GSM1677868; GSM1677876; GSM1677884 in GSE68633
source_species_code: HS
GEO_id: GSE68633
contributor: Orlando Musso
contrib_organization: INSERM (Institut National de la Santé et de la Recherche Médicale), France.
description_brief:
[cell repeats an earlier one in this file: 228 characters]

description_full:
  Methods: Liver progenitor cells were incubated in a WNT-enriched microenvironment for 72hrs (200 ng/ml mouse recombinant purified Wnt3A from R&D Systems). Gene pathways dependent on downstream _-catenin were studied by _-catenin knockdown with specific siRNA. Gene pathways blocked by extracellular SFRP-like Wnt inhibitors were studied by co-incubating cells with recombinant purified FZD8_CRD (300 ng/ml, from R&D Systems). Independent culture experiments performed in triplicate include untreated cells or cells incubated with scrambled siRNA or with _-catenin-specific siRNA or with FZD8_CRD, alone or in combination with Wnt3A. In the absence of Wnt in the microenvironnment, soluble FZD8_CRD may dimerize with other cell surface FZD_CRD domains.


systematic_name: M39016
source_species_code: HS
GEO_id: GSE97541
contributor: Russell Ryan
contrib_organization: University Of Michigan
description_brief:
  Genes upregulated by rapid Notch activation and linked to Notch TF binding peaks in mantle cell lymphoma cell lines.

description_full:
  Gain-of-function Notch mutations are recurrent in mature small B cell lymphomas such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). We identified Notch-activated genes via rapid washout of gamma secretase inhibitor in MCL cell lines with activating Notch gene rearrangements, or that had been pre-stimulated by immobilized Notch ligand. We performed integrative analysis of Notch-regulated transcripts, genomic binding of Notch transcription factor complexes, and genome conformation data to identify direct Notch target genes in MCL cell lines. Likely indirect target genes (MYC-activated genes) were excluded by Notch activation experiments conducted in a cell line in which MYC expression was independent of Notch due to a genomic rearrangement of the MYC locus. This B cell Notch regulome is largely controlled through Notch-bound distal enhancers and includes genes involved in B cell receptor and cytokine signaling. We show that the oncogene MYC sustains proliferation of Notch-dependent MCL cell lines via a Notch-regulated lineage-restricted enhancer complex. Expression of direct Notch target genes is associated with Notch activity in an MCL xenograft model and in CLL lymph node biopsies.

exact_source:
  Table S4. Linkage Analysis for Notch-Activated Genes and Notch Transcription Complex Binding Peaks in MCL Cell Lines; Tab 1; Column A


systematic_name: M41739
exact_source: Table 1 (positive p63 Expression Score)
external_details_URL: https://doi.org/10.7554/elife.63266
source_species_code: HS
contributor: Martin Fischer
contrib_organization: Leibniz Institute on Aging, Fritz Lipmann Institute (FLI)
description_brief:
  Genes directly up-regulated by DeltaNp63, the p63 isoform that lacks the canonical transactivation domain and is predominantly expressed in stratifying epithelia, identified through a meta-analysis of both cell lines and primary cells.

description_full:
  To identify genes commonly regulated by DeltaNp63 across cell types and tissues, we employed a previously established meta-analysis approach. From 11 genome-wide studies, 16 publicly available gene expression datasets were integrated to generate a specific p63 Expression Score (the number of datasets that identify a gene as significantly up-regulated minus the number of datasets that identify the genes as significantly down-regulated). The gene expression profiling datasets have been obtained from knockdown (n = 12) or overexpression experiments (n = 4) of p63 in primary keratinocytes (n = 3), the keratinocyte cell line HaCaT (n = 2), the foreskin fibroblast cell line BJ (n = 1), the breast epithelial cell line MCF10A (n = 4), the squamous carcinoma cell lines H226 (n = 2), KYSE70 (n = 1), and FaDu (n = 1), as well as the pancreatic ductal adenocarcinoma cell lines BxPC3 (n = 1) and SUIT2 (n = 1) In addition, we integrated 20 p63 ChIP-seq datasets. Given the large number of p63-binding sites identified and the high variance in p63-dependent gene regulation, we employed conservative thresholds to identify high-probability target genes of DeltaNp63. We only used p63-binding sites supported by at least half of the datasets (>=10) that are linked through TSS proximity (within 5 kb) or double-elite enhancer:gene associations to genes with a p63 Expression Score >= 8.


systematic_name: M41740
external_details_URL: https://www.mdpi.com/1999-4923/13/1/77/htm
source_species_code: HS
GEO_id: GSE159034
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes upregulated in anti-TNF therapy non-responders vs. responders prior to the initiation of anti-TNF therapy

description_full:
  Background: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. Methods: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR. Results: Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <_0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). Conclusion: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.

exact_source:
  Table 3. List of genes expressed differentially between responders (R) and non-responders (NR) prior to initiation of anti-TNF treatment.


systematic_name: M41741
external_details_URL: https://www.mdpi.com/1999-4923/13/1/77/htm
source_species_code: HS
GEO_id: GSE159034
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes upregulated in anti-TNF therapy non-responders vs. responders after two weeks of anti-TNF therapy

description_full:
  Background: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. Methods: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR. Results: Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <_0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). Conclusion: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.

exact_source:
  Table 4. List of genes expressed differentially between responders (R) and non-responders (NR) after two weeks of anti-TNF treatment.


systematic_name: M41742
external_details_URL: https://www.mdpi.com/1999-4923/13/1/77/htm
source_species_code: HS
GEO_id: GSE159034
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes downregulated in anti-TNF therapy non-responders vs. responders after two weeks of anti-TNF therapy

description_full:
  Background: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. Methods: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR. Results: Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <_0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). Conclusion: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.

exact_source:
  Table 4. List of genes expressed differentially between responders (R) and non-responders (NR) after two weeks of anti-TNF treatment.


systematic_name: M41754
external_details_URL: https://doi.org/10.1158/2643-3230.bcd-20-0155
source_species_code: HS
GEO_id: GSE149238
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes upregulated in long-term hematopoietic stem cells (CD34+,CD38_,CD45RA_,CD90+,CD49f+) upon overexpression of Sphingosine-1-Phosphate Receptor 3 (S1PR3)

description_full:
  Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSCs by activating stress myelopoiesis, such roles in LSCs are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator that drives myeloid differentiation and activates inflammatory programs in both HSCs and LSCs. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across cohorts of patients with AML, each with distinct phenotypic and clinical properties. S1PR3 was high in LSCs and blasts of mature myeloid samples with linkages to chemosensitivity, whereas S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset.<BR/>Significance: S1PR3 is a novel regulator of myeloid fate in normal hematopoiesis that is heterogeneously expressed in AML. S1PR3 marks a subset of less primitive AML cases with a distinct inflammatory signature and therefore has clinical implications as both a therapeutic target and a biomarker to distinguish primitive from mature AML.

exact_source:
  Supplemental Table 3: LT-HSC DEGs. Differentially expressed genes with S1PR3 overexpression in LT-HSC and ST-HSC (q=0.05, fold change >1)


systematic_name: M41755
external_details_URL: https://doi.org/10.1158/2643-3230.bcd-20-0155
source_species_code: HS
GEO_id: GSE149238
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes upregulated in short-term hematopoietic stem cells (CD34+,CD38_,CD45RA_,CD90_,CD49f_) upon overexpression of Sphingosine-1-Phosphate Receptor 3 (S1PR3)

description_full:
  Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSCs by activating stress myelopoiesis, such roles in LSCs are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator that drives myeloid differentiation and activates inflammatory programs in both HSCs and LSCs. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across cohorts of patients with AML, each with distinct phenotypic and clinical properties. S1PR3 was high in LSCs and blasts of mature myeloid samples with linkages to chemosensitivity, whereas S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset.<BR/>Significance: S1PR3 is a novel regulator of myeloid fate in normal hematopoiesis that is heterogeneously expressed in AML. S1PR3 marks a subset of less primitive AML cases with a distinct inflammatory signature and therefore has clinical implications as both a therapeutic target and a biomarker to distinguish primitive from mature AML.

exact_source:
  Supplemental Table 3: ST-HSC DEGs. Differentially expressed genes with S1PR3 overexpression in LT-HSC and ST-HSC (q=0.05, fold change >1)


systematic_name: M41756
external_details_URL: https://doi.org/10.1158/2643-3230.bcd-20-0155
source_species_code: HS
GEO_id: GSE149238
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes downregulated in short-term hematopoietic stem cells (CD34+,CD38_,CD45RA_,CD90_,CD49f_) upon overexpression of Sphingosine-1-Phosphate Receptor 3 (S1PR3)

description_full:
  Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSCs by activating stress myelopoiesis, such roles in LSCs are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator that drives myeloid differentiation and activates inflammatory programs in both HSCs and LSCs. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across cohorts of patients with AML, each with distinct phenotypic and clinical properties. S1PR3 was high in LSCs and blasts of mature myeloid samples with linkages to chemosensitivity, whereas S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset.<BR/>Significance: S1PR3 is a novel regulator of myeloid fate in normal hematopoiesis that is heterogeneously expressed in AML. S1PR3 marks a subset of less primitive AML cases with a distinct inflammatory signature and therefore has clinical implications as both a therapeutic target and a biomarker to distinguish primitive from mature AML.

exact_source:
  Supplemental Table 3: ST-HSC DEGs. Differentially expressed genes with S1PR3 overexpression in LT-HSC and ST-HSC (q=0.05, fold change >-1)


description_brief: Genes up-regulated in hepatoblastoma (HB) tumors as compared with non-tumor (NT) adjacent tissue.
systematic_name: M45033
exact_source: Supplementary Table 3: FDR<0.00001, FC>=2
external_details_URL: https://www.sciencedirect.com/science/article/pii/S0168827820301872?via%3Dihub
source_species_code: HS
GEO_id: GSE132219
contributor: Carolina Armengol
contrib_organization: Germans Trias i Pujol Research Institute (IGTP)
description_full:
  Background & Aims: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB.<br/>Methods: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies.<br/>Results: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth.<br/>Conclusions: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB.


systematic_name: M45035
exact_source: Supplementary Table 4; Enriched genes in HB
external_details_URL: https://www.sciencedirect.com/science/article/pii/S0168827820301872?via%3Dihub
source_species_code: HS
GEO_id: GSE132219
contributor: Carolina Armengol
contrib_organization: Germans Trias i Pujol Research Institute (IGTP)
description_brief:
  Genes enriched in locus DLK1-DIO3 at 14q32 in hepatoblastoma (HB) as compared with non-tumor (NT) adjacent tissue assessed by Human Transcriptome Array (HTA).

description_full:
  Background & Aims: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB.


systematic_name: M45036
external_details_URL: https://www.sciencedirect.com/science/article/pii/S0168827820301872?via%3Dihub
source_species_code: HS
GEO_id: GSE132219
contributor: Carolina Armengol
contrib_organization: Germans Trias i Pujol Research Institute (IGTP)
description_brief:
  Genes hypermethylated and downexpressed in hepatoblastoma (HB) tumors as compared with non-tumor (NT) adjacent tissue assessed by Infinium MethylationEPIC 850K array and Human Transcriptome Array 2.0 & RNA-sequencing.

description_full:
  Background & Aims: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB.

exact_source:
  Supplementary Table 6; Methylation array:FDR p<0.0001 and __>=0.20; HTA 2.0: FDR p<0.05 and FC<=-2; RNAseq: FDR p<0.05 and FC<=-2


systematic_name: M45037
external_details_URL: https://www.sciencedirect.com/science/article/pii/S0168827820301872?via%3Dihub
source_species_code: HS
GEO_id: GSE132219
contributor: Carolina Armengol
contrib_organization: Germans Trias i Pujol Research Institute (IGTP)
description_brief:
  Genes hypomethylated and overexpressed in hepatoblastoma (HB) tumors as compared with non-tumor (NT) adjacent tissue assessed by Infinium MethylationEPIC 850K array and Human Transcriptome Array 2.0 & RNA-sequencing.

description_full:
  Background & Aims: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB.

exact_source:
  Supplementary Table 6; Methylation array:FDR p<0.0001 and __<-0.20; HTA 2.0: FDR p<0.05 and FC>=2; RNAseq: FDR p<0.05 and FC>=2


systematic_name: M45038
exact_source: Supplementary Table 9; FDR F-Test p<0.00001, FC MRS3vsMRS1 >=2 & FC MRS3vsMRS2 >= 2
external_details_URL: https://www.sciencedirect.com/science/article/pii/S0168827820301872?via%3Dihub
source_species_code: HS
GEO_id: GSE132219
contributor: Carolina Armengol
contrib_organization: Germans Trias i Pujol Research Institute (IGTP)
description_brief:
  Genes significantly upregulated in the high-risk Molecular Risk Stratification (MRS-3) hepatoblastoma (HB) as compared with intermediate-risk (MRS-2) and low-risk (MRS-1) molecular HBs, assessed by Human Transcriptome Array (HTA).

description_full:
[cell repeats an earlier one in this file: 372 characters]


systematic_name: M45039
exact_source: Supplementary Table 9; F-Test p<0.00001, FC MRS3vsMRS1<=-2 & FC MRS3vsMRS2<=-2
external_details_URL: https://www.sciencedirect.com/science/article/pii/S0168827820301872?via%3Dihub
source_species_code: HS
GEO_id: GSE132219
contributor: Carolina Armengol
contrib_organization: Germans Trias i Pujol Research Institute (IGTP)
description_brief:
  Genes significantly down-regulated in the high-risk Molecular Risk Stratification (MRS-3) hepatoblastoma (HB) as compared with intermediate-risk (MRS-2) and low-risk (MRS-1) molecular HBs, assessed by Human Transcriptome Array (HTA).

description_full:
[cell repeats an earlier one in this file: 372 characters]


description_brief: Genes up-regulated in natural killer cells.
systematic_name: M45040
source_species_code: HS
contributor: Dharmesh D. Bhuva
contrib_organization: Walter and Eliza Hall Institute of Medical Research
description_full:
  A preliminary gene set was obtained by combining the CIBERSORT (LM22) and Tosolini et al (LM7) gene sets for natural killer (NK) cells, together with a selection of marker genes from mouse NK cell studies (Huntington gene lists). Genes were filtered using by using bulk RNA-seq (GSE60424; via differential expression between NK cells and other sorted blood cell populations) and single cell RNA-seq (GSE72056; comparing various percentile thresholds between immune cell subsets) to select genes with particularly high transcript abundance within NK cells. The resulting gene set was further filtered to remove any genes which also show moderate-high expression within solid tumor cell lines from the Cancer Cell Line Encyclopedia. Genes filtered at various steps are labelled in Table S1 from the original publication (see EXTERNAL_DETAILS_URL). For a graphical summary please refer to Supplementary Figure S2 from DOI: 10.1158/2326-6066.CIR-18-0500

exact_source:
  Supplementary Table 1 - Official gene symbols (HGNC) for our 20 NK signature genes and a subset of the results leading to their inclusion during curation, in particular bulk RNA-seq differential expression results and comparison to T cells for single-cell RNA-seq data from Tirosh et al (2016). For further details please refer to the Materials and Methods. LM22: CIBERSORT LM22 lists; LM7: Tosolini et al LM7 list.

external_details_URL:
  https://cancerimmunolres.aacrjournals.org/highwire/filestream/37099/field_highwire_adjunct_files/0/205802_2_supp_5410854_prn3pl.xlsx


systematic_name: M45041
exact_source: Table S7: OncoScore ranked table of top-target mRNAs with best interactions
source_species_code: HS
GEO_id: GSE185719
contributor: Danny Misiak
contrib_organization: Martin Luther University Halle-Wittenberg
description_brief:
  Genes up-regulated in anaplastic thyroid carcinoma and sharply distinguishing ATC from other thyroid carcinomas.

description_full:
  Anaplastic thyroid carcinoma (ATC) is the most fatal and rapidly evolving endocrine malignancy invading the head and neck region and accounts for up to 50% of thyroid cancer-associated deaths. Deregulation of the microRNA (miRNA) expression promotes thyroid carcinoma progression by modulating the reorganization of the ATC transcriptome. Here, we applied comparative miRNA-mRNA sequencing on a cohort of 28 thyroid carcinomas to unravel the association of deregulated miRNA and mRNA expression. This identified 85 miRNAs significantly deregulated in ATC. By establishing a new analysis pipeline, we unraveled 85 prime miRNA-mRNA interactions supporting the downregulation of candidate tumor suppressors and the upregulation of bona fide oncogenes such as survivin (BIRC5) in ATC. This miRNA-dependent reprogramming of the ATC transcriptome provided an mRNA signature comprising 65 genes sharply distinguishing ATC from other thyroid carcinomas. The validation of the deregulated protein expression in an independent thyroid carcinoma cohort demonstrates that miRNA-dependent oncogenes comprised in this signature, the transferrin receptor TFRC (CD71) and the E3-ubiquitin ligase DTL, are sharply upregulated in ATC. This upregulation is sufficient to distinguish ATC even from poorly differentiated thyroid carcinomas (PDTC). In sum, these findings provide new diagnostic tools and a robust resource to explore the key miRNA-mRNA regulation underlying the progression of thyroid carcinoma.


systematic_name: M45042
exact_source: Table S7: OncoScore ranked table of top-target mRNAs with best interactions
source_species_code: HS
GEO_id: GSE185719
contributor: Danny Misiak
contrib_organization: Martin Luther University Halle-Wittenberg
description_brief:
  Genes down-regulated in anaplastic thyroid carcinoma and sharply distinguishing ATC from other thyroid carcinomas.

description_full:
  Anaplastic thyroid carcinoma (ATC) is the most fatal and rapidly evolving endocrine malignancy invading the head and neck region and accounts for up to 50% of thyroid cancer-associated deaths. Deregulation of the microRNA (miRNA) expression promotes thyroid carcinoma progression by modulating the reorganization of the ATC transcriptome. Here, we applied comparative miRNA-mRNA sequencing on a cohort of 28 thyroid carcinomas to unravel the association of deregulated miRNA and mRNA expression. This identified 85 miRNAs significantly deregulated in ATC. By establishing a new analysis pipeline, we unraveled 85 prime miRNA-mRNA interactions supporting the downregulation of candidate tumor suppressors and the upregulation of bona fide oncogenes such as survivin (BIRC5) in ATC. This miRNA-dependent reprogramming of the ATC transcriptome provided an mRNA signature comprising 65 genes sharply distinguishing ATC from other thyroid carcinomas. The validation of the deregulated protein expression in an independent thyroid carcinoma cohort demonstrates that miRNA-dependent oncogenes comprised in this signature, the transferrin receptor TFRC (CD71) and the E3-ubiquitin ligase DTL, are sharply upregulated in ATC. This upregulation is sufficient to distinguish ATC even from poorly differentiated thyroid carcinomas (PDTC). In sum, these findings provide new diagnostic tools and a robust resource to explore the key miRNA-mRNA regulation underlying the progression of thyroid carcinoma.


description_brief: Genes upregulated in senescent cells: Senescence-associated secretory phenotype (SASP).
systematic_name: M45803
exact_source: Supplementary Data 1
source_species_code: HS
GEO_id: GSE72815, GSE141595
contributor: Dominik Saul
contrib_organization: Mayo Clinic Rochester, MN, USA
description_full:
  Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.


systematic_name: M46416
source_species_code: HS
contributor: Augustin Luna
contrib_organization: Broad Institute
description_brief:
  Epithelial phenotype associated genes from an Epithelial-Mesenchymal Transition (EMT) gene set allowing sample stratification into epithelial, mesenchymal, and epithelial-mesenchymal categories initially developed on the NCI-60 cell line collection.

description_full:
  Expression-correlated genes were derived from data for the NCI-60 human tumor cell lines, as well as data from the Broad Institute's CCLE cell lines. NCI-60 cell lines that selectively expressed a mutually correlated subset of tight junction genes served as a signature for epithelial-like cancer cells. Those signature cell lines served as a seed to derive other correlated genes, many of which had various other epithelial-related functions. Literature survey yielded molecular interaction and function information about those genes, from which molecular interaction maps were assembled. Many of the genes had epithelial functions unrelated to tight junctions, demonstrating that new function categories were elicited. The most highly correlated genes were implicated in the following epithelial functions: interactions at tight junctions (CLDN7, CLDN4, CLDN3, MARVELD3, MARVELD2, TJP3, CGN, CRB3, LLGL2, EPCAM, LNX1); interactions at adherens junctions (CDH1, ADAP1, CAMSAP3); interactions at desmosomes (PPL, PKP3, JUP); transcription regulation of cell-cell junction complexes (GRHL1 and 2); epithelial RNA splicing regulators (ESRP1 and 2); epithelial vesicle traffic (RAB25, EPN3, GRHL2, EHF, ADAP1, MYO5B); epithelial Ca(+2) signaling (ATP2C2, S100A14, BSPRY); terminal differentiation of epithelial cells (OVOL1 and 2, ST14, PRSS8, SPINT1 and 2); maintenance of apico-basal polarity (RAB25, LLGL2, EPN3).

exact_source:
  PMID: 30553813 FIG 7A. Genes associated with the Epithelial phenotype of the EMT Gene Expression Signature


systematic_name: M46417
source_species_code: HS
contributor: Augustin Luna
contrib_organization: Broad Institute
description_brief:
  Mesenchymal phenotype associated genes from an Epithelial-Mesenchymal Transition (EMT) gene set allowing sample stratification into epithelial, mesenchymal, and epithelial-mesenchymal categories initially developed on the NCI-60 cell line collection.

description_full:
  Expression-correlated genes were derived from data for the NCI-60 human tumor cell lines, as well as data from the Broad Institute's CCLE cell lines. NCI-60 cell lines that selectively expressed a mutually correlated subset of tight junction genes served as a signature for epithelial-like cancer cells. Those signature cell lines served as a seed to derive other correlated genes, many of which had various other epithelial-related functions. Literature survey yielded molecular interaction and function information about those genes, from which molecular interaction maps were assembled. Many of the genes had epithelial functions unrelated to tight junctions, demonstrating that new function categories were elicited. The most highly correlated genes were implicated in the following epithelial functions: interactions at tight junctions (CLDN7, CLDN4, CLDN3, MARVELD3, MARVELD2, TJP3, CGN, CRB3, LLGL2, EPCAM, LNX1); interactions at adherens junctions (CDH1, ADAP1, CAMSAP3); interactions at desmosomes (PPL, PKP3, JUP); transcription regulation of cell-cell junction complexes (GRHL1 and 2); epithelial RNA splicing regulators (ESRP1 and 2); epithelial vesicle traffic (RAB25, EPN3, GRHL2, EHF, ADAP1, MYO5B); epithelial Ca(+2) signaling (ATP2C2, S100A14, BSPRY); terminal differentiation of epithelial cells (OVOL1 and 2, ST14, PRSS8, SPINT1 and 2); maintenance of apico-basal polarity (RAB25, LLGL2, EPN3).

exact_source:
  PMID: 30553813 FIG 7A. Genes associated with the Mesenchymal phenotype of the EMT Gene Expression Signature


systematic_name: M46420
source_species_code: HS
GEO_id: GSE183200
contributor: Amina Zoubeidi
contrib_organization: University of British Columbia and Vancouver Prostate Centre
description_brief:
  Genes bound by ASCL1 in prostate cancer cell lines, and up-regulated in ASCL1 positive patient-driven xenografts.

description_full:
  We performed ChIPseq analysis on ASCL1 positive neuroendocrine prostate cancer cell lines 42D-ENZR and two sets of NCI-H660 as well as in LNCaP cells overexpressing ASCL1. Several thousand ASCL1 binding sites were identified following analysis of each ChIPseq. A total of 2,360 genes annotated to ASCL1 were found common among the four samples. We identified ASCL1 binding at bona fide ASCL1 regulated genes such as INSM1, ID4, HES6, CHGA and DLL4. Integrated ASCL1 ChIPseq data with transcriptomics (RNAseq) data, to identify a consensus ASCL1 transcriptome, we utilized RNAseq from publicly available ASCL1 (+) vs ASCL1 (?) patient driven xenografts from Labreque et al, 2019. 160 ASCL1-bound genes identified in prostate cancer ChIPseq studies also exhibited significantly higher mRNA expression (log2FoldChange?>?2) in the ASCL1 (+) compared to ASCL1 (?) LuCaP PDXs. These genes represent targets of ASCL1, where expression is likely directly regulated by ASCL1 binding.

exact_source:
  ChIPseq from current publication PMID (35477723), ChIPseq from Baca et al, 2021 (PMID 34599169) and RNAseq from Labreque et al, 2019 (PMID 31361600)


systematic_name: M47981
external_details_URL: https://doi.org/10.1074/mcp.M111.014647
source_species_code: HS
GEO_id: MSV000078494
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Tumor-derived matrisome proteins exclusively detected in poorly metastatic melanoma human-to-mouse xenografts (A375) in comparison to highly metastatic melanoma human-to-mouse xenografts (A375_MA2).

description_full:
  We employed a proteomic strategy developed to characterize the in-vivo ECM composition of normal tissues and tumors using enrichment of protein extracts for ECM components and subsequent analysis by mass spectrometry. We grew subcutaneous tumors by injection into NOD/SCID/IL2R? mice of A375 human melanoma cells (poorly metastatic) or their highly metastatic derivatives MA2. The tumors were dissected 5 weeks later, and the tumor ECM was enriched and analyzed using mass spectrometry. We define the tumor ECM as the ensemble of ECM proteins and ECM-associated proteins found in two independent samples. A challenging question when studying the tumor microenvironment is to understand the origin of the tumor ECM; that is, whether the tumor ECM is produced and secreted by the tumor cells themselves, by the stromal cells or by both compartments. To address this question, we pursued the analysis of the melanoma xenografts described above, by identifying the origin of each protein.  In order to be able to identify without ambiguity the origin of each protein, we required that proteins needed to be detected in two independent samples with at least two species-specific peptides in one of them. Using this strategy, we identified for each tumor type a set of matrisome proteins exclusively secreted by the (human) tumor cells, and another set exclusively secreted by the (murine) stromal cells. This gene set lists the matrisome proteins (based on the criteria mentioned above) secreted by the tumor cells in A375 tumors and not in MA2 tumors.

exact_source:
  mcp.M111.014647-6, Figure 5A. The tumor extracellular matrix is secreted by both tumor cells and stromal cells and differs with metastatic potential.


systematic_name: M47982
external_details_URL: https://doi.org/10.1074/mcp.M111.014647
source_species_code: HS
GEO_id: MSV000078494
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins exclusively detected in poorly metastatic melanoma human-to-mouse xenografts (A375) in comparison to highly metastatic melanoma human-to-mouse xenografts (A375_MA2).

description_full:
  We employed a proteomic strategy developed to characterize the in-vivo ECM composition of normal tissues and tumors using enrichment of protein extracts for ECM components and subsequent analysis by mass spectrometry. We grew subcutaneous tumors by injection into NOD/SCID/IL2R? mice of A375 human melanoma cells (poorly metastatic) or their highly metastatic derivatives MA2. The tumors were dissected 5 weeks later, and the tumor ECM was enriched and analyzed using mass spectrometry. We define the tumor ECM as the ensemble of ECM proteins and ECM-associated proteins found in two independent samples. A challenging question when studying the tumor microenvironment is to understand the origin of the tumor ECM; that is, whether the tumor ECM is produced and secreted by the tumor cells themselves, by the stromal cells or by both compartments. To address this question, we pursued the analysis of the melanoma xenografts described above, by identifying the origin of each protein.  In order to be able to identify without ambiguity the origin of each protein, we required that proteins needed to be detected in two independent samples with at least two species-specific peptides in one of them. Using this strategy, we identified for each tumor type a set of matrisome proteins exclusively secreted by the (human) tumor cells, and another set exclusively secreted by the (murine) stromal cells. This gene set lists the matrisome proteins (based on the criteria mentioned above) secreted by the tumor cells and stromal cells in A375 tumors and not in MA2 tumors.

exact_source:
  mcp.M111.014647-6, Figure 5A. The tumor extracellular matrix is secreted by both tumor cells and stromal cells and differs with metastatic potential.


systematic_name: M47983
external_details_URL: https://doi.org/10.1074/mcp.M111.014647
source_species_code: HS
GEO_id: MSV000078494
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Tumor-cell-derived matrisome proteins exclusively detected in highly metastatic melanoma human-to-mouse xenografts (A375_MA2) in comparison to poorly metastatic melanoma human-to-mouse xenografts (A375).

description_full:
  We employed a proteomic strategy developed to characterize the in-vivo ECM composition of normal tissues and tumors using enrichment of protein extracts for ECM components and subsequent analysis by mass spectrometry. We grew subcutaneous tumors by injection into NOD/SCID/IL2R? mice of A375 human melanoma cells (poorly metastatic) or their highly metastatic derivatives MA2. The tumors were dissected 5 weeks later, and the tumor ECM was enriched and analyzed using mass spectrometry. We define the tumor ECM as the ensemble of ECM proteins and ECM-associated proteins found in two independent samples. A challenging question when studying the tumor microenvironment is to understand the origin of the tumor ECM; that is, whether the tumor ECM is produced and secreted by the tumor cells themselves, by the stromal cells or by both compartments. To address this question, we pursued the analysis of the melanoma xenografts described above, by identifying the origin of each protein.  In order to be able to identify without ambiguity the origin of each protein, we required that proteins needed to be detected in two independent samples with at least two species-specific peptides in one of them. Using this strategy, we identified for each tumor type a set of matrisome proteins exclusively secreted by the (human) tumor cells, and another set exclusively secreted by the (murine) stromal cells. This gene set lists the matrisome proteins (based on the criteria mentioned above) secreted by the tumor cells in MA2 tumors and not in A375 tumors.

exact_source:
  mcp.M111.014647-6,  Figure 5B. The tumor extracellular matrix is secreted by both tumor cells and stromal cells and differs with metastatic potential.


systematic_name: M47984
external_details_URL: https://doi.org/10.1074/mcp.M111.014647
source_species_code: HS
GEO_id: MSV000078501
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins exclusively detected in highly metastatic melanoma human-to-mouse xenografts (A375_MA2) in comparison to poorly metastatic melanoma human-to-mouse xenografts (A375).

description_full:
  We employed a proteomic strategy developed to characterize the in-vivo ECM composition of normal tissues and tumors using enrichment of protein extracts for ECM components and subsequent analysis by mass spectrometry. We grew subcutaneous tumors by injection into NOD/SCID/IL2R? mice of A375 human melanoma cells (poorly metastatic) or their highly metastatic derivatives MA2. The tumors were dissected 5 weeks later, and the tumor ECM was enriched and analyzed using mass spectrometry. We define the tumor ECM as the ensemble of ECM proteins and ECM-associated proteins found in two independent samples. A challenging question when studying the tumor microenvironment is to understand the origin of the tumor ECM; that is, whether the tumor ECM is produced and secreted by the tumor cells themselves, by the stromal cells or by both compartments. To address this question, we pursued the analysis of the melanoma xenografts described above, by identifying the origin of each protein.  In order to be able to identify without ambiguity the origin of each protein, we required that proteins needed to be detected in two independent samples with at least two species-specific peptides in one of them. Using this strategy, we identified for each tumor type a set of matrisome proteins exclusively secreted by the (human) tumor cells, and another set exclusively secreted by the (murine) stromal cells. This gene set lists the matrisome proteins (based on the criteria mentioned above) secreted by the tumor cells and stromal cells in MA2 tumors and not in A375 tumors.

exact_source:
  mcp.M111.014647-6,  Figure 5B. The tumor extracellular matrix is secreted by both tumor cells and stromal cells and differs with metastatic potential.


systematic_name: M47985
external_details_URL: https://doi.org/10.7554/eLife.01308
source_species_code: HS
GEO_id: MSV000078535
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Tumor-cell-derived matrisome proteins exclusively detected in poorly metastatic breast cancer human-to-mouse xenografts (MDA-MB-231) in comparison to highly metastatic breast cancer human-to-mouse xenografts (MDA-MB-231_LM2)

description_full:
  To define the ECM composition of tissues and tumors, we have empolyed a proteomics-based method to enrich and identify ECM proteins and coupled it with a bioinformatic annotation of the  matrisome  defined as the ensemble of ECM and ECM-associated proteins. To identify ECM proteins important for breast cancer progression and metastasis formation, we used a xenograft model where human breast cancer cells of differing metastatic potenital were orthotopically injected into the mouse mammary fat pad. The poorly metastatic MDA-MB-231 cell line was established from cells isolated from a sample from a triple-negative breast cancer patient. The highly metastatic MDA-MB-231-LM2 line (denoted LM2), was previously selected and characterized for increased metastatic potential to the lungs. 6.5 weeks post-injection, the primary tumors were harvested, ECM proteins were enriched from tumors, and the composition of the ECM-enriched fractions obtained was characterized by mass spectrometry. We define the matrisome of a tumor as the ensemble of proteins detected in two independent biological replicates and by at least two peptides in one of the two replicates. Using this proteomics approach we show that both the tumor cells and the stromal cells contribute in characteristic ways to the production of the tumor ECM. Moreover, we show that both tumor- and stroma-derived proteins differ between tumors of different metastatic potential. Comparison of the matrisomes of MDA-MB-231 tumors and LM2 tumors identifies ECM proteins characteristic of poorly and highly metastatic tumors. This gene set lists the matrisome proteins secreted by the tumor cells in MDA-MB-231 tumors and not from LM2 tumors.

exact_source:
  elife-01308-fig3-data1-v1.xlsx, Figure 3C. The tumor extracellular matrix is secreted by both tumor cells and stromal cells and differs with the tumor s metastatic potential.


systematic_name: M47986
external_details_URL: https://doi.org/10.7554/eLife.01308
source_species_code: HS
GEO_id: MSV000078535
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins exclusievly detected in poorly metastatic breast cancer human-to-mouse xenografts (MDA-MB-231) in comparison to highly metastatic breast cancer human-to-mouse xenografts (MDA-MB-231_LM2).

description_full:
  To define the ECM composition of tissues and tumors, we have empolyed a proteomics-based method to enrich and identify ECM proteins and coupled it with a bioinformatic annotation of the  matrisome  defined as the ensemble of ECM and ECM-associated proteins. To identify ECM proteins important for breast cancer progression and metastasis formation, we used a xenograft model where human breast cancer cells of differing metastatic potenital were orthotopically injected into the mouse mammary fat pad. The poorly metastatic MDA-MB-231 cell line was established from cells isolated from a sample from a triple-negative breast cancer patient. The highly metastatic MDA-MB-231-LM2 line (denoted LM2), was previously selected and characterized for increased metastatic potential to the lungs. 6.5 weeks post-injection, the primary tumors were harvested, ECM proteins were enriched from tumors, and the composition of the ECM-enriched fractions obtained was characterized by mass spectrometry. We define the matrisome of a tumor as the ensemble of proteins detected in two independent biological replicates and by at least two peptides in one of the two replicates. Using this proteomics approach we show that both the tumor cells and the stromal cells contribute in characteristic ways to the production of the tumor ECM. Moreover, we show that both tumor- and stroma-derived proteins differ between tumors of different metastatic potential. Comparison of the matrisomes of MDA-MB-231 tumors and LM2 tumors identifies ECM proteins characteristic of poorly and highly metastatic tumors. This gene set lists the matrisome proteins secreted by the tumor cells and stromal cells in MDA-MB-231 tumors and not from LM2 tumors.

exact_source:
  elife-01308-fig3-data1-v1.xlsx, Figure 3C. The tumor extracellular matrix is secreted by both tumor cells and stromal cells and differs with the tumor s metastatic potential.


systematic_name: M47987
external_details_URL: https://doi.org/10.7554/eLife.01308
source_species_code: HS
GEO_id: MSV000078535
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Tumor-cell-derived matrisome proteins exclusively detected in highly metastatic breast cancer human-to-mouse xenografts (MDA-MB-231_LM2) in comparison to poorly metastatic breast cancer human-to-mouse xenografts (MDA-MB-231).

description_full:
  To define the ECM composition of tissues and tumors, we have empolyed a proteomics-based method to enrich and identify ECM proteins and coupled it with a bioinformatic annotation of the  matrisome  defined as the ensemble of ECM and ECM-associated proteins. To identify ECM proteins important for breast cancer progression and metastasis formation, we used a xenograft model where human breast cancer cells of differing metastatic potenital were orthotopically injected into the mouse mammary fat pad. The poorly metastatic MDA-MB-231 cell line was established from cells isolated from a sample from a triple-negative breast cancer patient. The highly metastatic MDA-MB-231-LM2 line (denoted LM2), was previously selected and characterized for increased metastatic potential to the lungs. 6.5 weeks post-injection, the primary tumors were harvested, ECM proteins were enriched from tumors, and the composition of the ECM-enriched fractions obtained was characterized by mass spectrometry. We define the matrisome of a tumor as the ensemble of proteins detected in two independent biological replicates and by at least two peptides in one of the two replicates. Using this proteomics approach we show that both the tumor cells and the stromal cells contribute in characteristic ways to the production of the tumor ECM. Moreover, we show that both tumor- and stroma-derived proteins differ between tumors of different metastatic potential. Comparison of the matrisomes of MDA-MB-231 tumors and LM2 tumors identifies ECM proteins characteristic of poorly and highly metastatic tumors. This gene set lists the matrisome proteins secreted by the tumor cells in LM2 tumors and not from MDA-MB-231 tumors.

exact_source:
  elife-01308-fig3-data1-v1.xlsx, Figure 3D. The tumor extracellular matrix is secreted by both tumor cells and stromal cells and differs with the tumor s metastatic potential.


systematic_name: M47988
external_details_URL: https://doi.org/10.7554/eLife.01308
source_species_code: HS
GEO_id: MSV000078535
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins exclusively detected in highly metastatic breast cancer human-to-mouse xenografts (MDA-MB-231_LM2) in comparison to poorly metastatic breast cancer human-to-mouse xenografts (MDA-MB-231).

description_full:
  To define the ECM composition of tissues and tumors, we have empolyed a proteomics-based method to enrich and identify ECM proteins and coupled it with a bioinformatic annotation of the  matrisome  defined as the ensemble of ECM and ECM-associated proteins. To identify ECM proteins important for breast cancer progression and metastasis formation, we used a xenograft model where human breast cancer cells of differing metastatic potenital were orthotopically injected into the mouse mammary fat pad. The poorly metastatic MDA-MB-231 cell line was established from cells isolated from a sample from a triple-negative breast cancer patient. The highly metastatic MDA-MB-231-LM2 line (denoted LM2), was previously selected and characterized for increased metastatic potential to the lungs. 6.5 weeks post-injection, the primary tumors were harvested, ECM proteins were enriched from tumors, and the composition of the ECM-enriched fractions obtained was characterized by mass spectrometry. We define the matrisome of a tumor as the ensemble of proteins detected in two independent biological replicates and by at least two peptides in one of the two replicates. Using this proteomics approach we show that both the tumor cells and the stromal cells contribute in characteristic ways to the production of the tumor ECM. Moreover, we show that both tumor- and stroma-derived proteins differ between tumors of different metastatic potential. Comparison of the matrisomes of MDA-MB-231 tumors and LM2 tumors identifies ECM proteins characteristic of poorly and highly metastatic tumors. This gene set lists the matrisome proteins secreted by the tumor cells and stromal cells in LM2 tumors and not from MDA-MB-231 tumors.

exact_source:
  elife-01308-fig3-data1-v1.xlsx, Figure 3D. The tumor extracellular matrix is secreted by both tumor cells and stromal cells and differs with the tumor s metastatic potential.


systematic_name: M47989
external_details_URL: https://doi.org/10.1186/1471-2407-14-518
source_species_code: HS
GEO_id: MSV000078555
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins found differentially expressed in primary metastatic colon tumors in comparison to normal colon and normal liver.

description_full:
  In order to identify candidate biomarkers, we sought to define ECM signatures of metastatic colorectal cancers and their metastases to the liver. We obtained patient-matched metastatic colorectal cancer samples (primary tumor and paired metastases to liver) and normal colonic tissue from three patients from Massachusetts General Hospital s tissue bank. We also obtained normal liver tissue from healthy donors. We have used enrichment of ECM from human patient samples and proteomics to define the ECM composition of primary colon carcinomas and their metastases to liver in comparison with normal colon and liver samples. We defined, for each tissue or tumor type, its matrisome as the ensemble of proteins detected in at least two of the three patients studied. Based on these changes, we derived ECM protein signatures of primary colon carcinoma and primary colon tumor metastasis to liver. Comparisons of these signatures with available clinical gene expression array data show that subsets of these signatures correlate well with tumor progression and metastasis. Importantly, we identified subsets of tumor-specific proteins either characteristic of the colon tumor matrisome or characteristic of the metastasis matrisome. This gene set lists the matrisome proteins detected either exclusively or in significantly higher abundance in primary metastatic colon tumors compared to normal colon and liver.

exact_source:
  12885_2014_4731_MOESM2_ESM.xlsx, Figure 2E. Venn diagram shows comparisons among the metastatic colon cancer matrisomes (primary colon tumor and associated metastases to liver) and control tissue matrisomes (normal colon and normal liver)


systematic_name: M47990
external_details_URL: https://doi.org/10.1186/1471-2407-14-518
source_species_code: HS
GEO_id: MSV000078555
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins found differentially expressed in secondary colorectal liver metastatases in comparison to normal colon and normal liver.

description_full:
  In order to identify candidate biomarkers, we sought to define ECM signatures of metastatic colorectal cancers and their metastases to the liver. We obtained patient-matched metastatic colorectal cancer samples (primary tumor and paired metastases to liver) and normal colonic tissue from three patients from Massachusetts General Hospital s tissue bank. We also obtained normal liver tissue from healthy donors. We have used enrichment of ECM from human patient samples and proteomics to define the ECM composition of primary colon carcinomas and their metastases to liver in comparison with normal colon and liver samples. We defined, for each tissue or tumor type, its matrisome as the ensemble of proteins detected in at least two of the three patients studied. Based on these changes, we derived ECM protein signatures of primary colon carcinoma and primary colon tumor metastasis to liver. Comparisons of these signatures with available clinical gene expression array data show that subsets of these signatures correlate well with tumor progression and metastasis. Importantly, we identified subsets of tumor-specific proteins either characteristic of the colon tumor matrisome or characteristic of the metastasis matrisome. This gene set lists the matrisome proteins detected either exclusively or in significantly higher abundance in colorectal liver metastases compared to normal colon and liver.

exact_source:
  12885_2014_4731_MOESM2_ESM.xlsx, Figure 2E. Venn diagram shows comparisons among the metastatic colon cancer matrisomes (primary colon tumor and associated metastases to liver) and control tissue matrisomes (normal colon and normal liver)


systematic_name: M47991
external_details_URL: https://doi.org/10.1038/leu.2017.102
source_species_code: HS
GEO_id: MSV000080451
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins detected in newly-diagnosed multiple myeloma (MM) patient bone marrow (BM) compared to MGUS and relapsed MM-BM.

description_full:
  We aimed to define the proteomic signature of bone marrow (BM) extracellular matrices (ECMs) obtained from patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM), as compared with healthy donor-derived BM ECMs. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with MGUS, newly diagnosed and relapsed MM, compared with healthy donor-derived BM ECM. Peptide abundance, spectral count, number of unique peptides, and the number of identified proteins within the whole BM were measured for both healthy donors and patients with MGUS or MM, either at first diagnosis or at relapse. We began by defining the matrisome of healthy donor-derived BM as the ensemble of proteins detected in at least three independent biological replicates (that is, patients) and by at least three peptides in one of the replicates. Subsequently, we sought to define the proteomic signature for BM ECMs derived from MGUS patients using the same criteria. Comparing the these matrisomes identified proteins expressed by all four groups as well as proteins that are not present until later stages of the disease. This gene set lists the matrisome proteins detected in newly-diagnosed MM patient BM compared to MGUS and relapsed MM-BM.

exact_source:
  Supplementary Table S2, Figure 4. Comparison of the matrisome of normal and diseased bone marrow samples.


systematic_name: M47993
exact_source: Supplementary Table S1D
external_details_URL: https://doi.org/10.1021/acs.jproteome.7b00191
source_species_code: HS
GEO_id: PXD005554
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins detected in significantly different abundance in omentum metastases from high grade serous ovarian cancer (HGSOC) compared to normal omentum.

description_full:
  Patient samples were kindly donated by women with high-grade serous ovarian cancer (HGSOC). We optimized protocols to solubilize ECM proteins from normal or tumor tissues, digest the proteins into peptides, analyze ECM peptides by mass spectrometry, and interpret the mass spectrometric data. Using LC-MS/MS, we analyzed ECM-enriched samples of disease-free omentum from patients with non-metastatic ovarian cancer and HGSOC-derived omental metastasis samples. A second critical step of the approach was the identification and annotation of the ECM components, or matrisome, in large proteomic data sets. The curation of this signature utilized crude ECM extracts rather than urea-soluable extracts. This gene set lists the matrisome proteins detected in significantly differential abundance in omentum metastases from high grade serous ovarian cancer (HGSOC) compared to normal omentum.


systematic_name: M47994
exact_source: Supplemental Table S1 G
external_details_URL: https://doi.org/10.1038/s43018-021-00291-9
source_species_code: HS
GEO_id: PXD019185
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins detected exclusively in highly proliferative head-and-neck squamous cell carcinoma human-to-mouse xenografts (T-Hep3) compared to dormant head-and-neck squamous cell carcinoma human-to-mouse xenografts (D-Hep3).

description_full:
  By using ECM proteomics we have defined the matrisome of dormant cancer cells vs proliferative cancer cells of head and neck squamous cell carcinoma (HNSCC). To do so, we used established cellular dormancy models and their proliferative counterparts: proliferative (T-HEp3) and dormant (D-HEp3) HNSCC. To investigate the matrisome composition of these dormant and proliferative tumors, we performed ECM-enriched mass spectrometry using decellularized T-HEp3 tumors and D-HEp3 dormant nodules grown in mice. Analysis of indolent D-HEp3 dormant nodules and aggressive T-HEp3 tumors grown in mice show a significant dysregulation of the matrisome signature. This gene set lists the matrisome proteins detected exclusively in highly proliferative HNSCC human-to-mouse xenograft compared to dormant HNSCC human-to-mouse xenograft. We further excluded proteins that were detected in only one of the three proliferative samples.


systematic_name: M47995
exact_source: Supplemental Table S1 G
external_details_URL: https://doi.org/10.1038/s43018-021-00291-9
source_species_code: HS
GEO_id: PXD019185
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Tumor-cell-derived matrisome proteins detected exclusively in highly proliferative head-and-neck squamous cell carcinoma human-to-mouse xenografts (T-Hep3) compared to dormant head-and-neck squamous cell carcinoma human-to-mouse xenografts (D-Hep3).

description_full:
  By using ECM proteomics we have defined the matrisome of dormant cancer cells vs proliferative cancer cells of head and neck squamous cell carcinoma (HNSCC). To do so, we used established cellular dormancy models and their proliferative counterparts: proliferative (T-HEp3) and dormant (D-HEp3) HNSCC. To investigate the matrisome composition of these dormant and proliferative tumors, we performed ECM-enriched mass spectrometry using decellularized T-HEp3 tumors and D-HEp3 dormant nodules grown in mice. Analysis of indolent D-HEp3 dormant nodules and aggressive T-HEp3 tumors grown in mice show a significant dysregulation of the matrisome signature.  The human-in-mouse xenograft system used further allowed us to determine the relative contribution of tumor cells (human peptide sequences) and stromal cells (murine peptide sequences) to the production of the matrisome. This gene set lists the tumor-derived matrisome proteins detected exclusively in highly proliferative HNSCC human-to-mouse xenograft compared to dormant HNSCC human-to-mouse xenograft. We further excluded proteins that were detected in only one of the three proliferative samples.


systematic_name: M47996
exact_source: NIHMS1558781-supplement-4 Figure 4A & 5A
external_details_URL: https://doi.org/10.1158/0008-5472.CAN-19-2961
source_species_code: HS
GEO_id: MSV000084023
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Tumor cell-derived matrisome proteins found in significantly higher abundance in TNBC bone metastasis niche compared to TNBC brain, liver and lung metastatic niches.

description_full:
  We have previously developed methods for enriching tissue samples for their ECM protein content by taking advantage of the relative insolubility of the ECM, and we have used these techniques in conjunction with mass spectrometry-based proteomics to profile the  matrisome,  the complete collection of both core ECM and ECM-associated proteins, in several different cancers. Here we define and compare the ECM components of metastatic niches and how they differ among the specific secondary sites common in TNBC. For this purpose, we use as a model the MDA-MB-231 human TNBC cell line, originally derived from a patient pleural effusion (24), which is capable of metastasizing to the brain, lungs, liver and bone marrow in mouse xenografts. We identify which ECM proteins are commonly elevated at multiple different metastatic sites, and which are preferentially elevated in particular sites. We investigate how these specific ECM proteins, as well as the tumor matrix overall, are differentially produced by the tumor and stromal cells; in this paper, we use  stromal  to include all cells in the tumor that are not tumor cells. These comparisons did not simply identify the most elevated proteins in each tissue, but rather the proteins most significantly different in abundance in one tissue relative to all others. Separate analyses were conducted for tumor-cell-derived (human) and stroma-derived (mouse) proteins. In this study, we performed an unbiased, quantitative mass spectrometric survey of ECM proteins present in MDA-MB-231 breast cancer xenograft metastases to the brain, lungs, liver and bone marrow. This gene set lists the tumor-cell secreted matrisome proteins found in significantly higher abundance in TNBC bone metastasis niche compared to TNBC brain, liver and lung metastatic niches.


systematic_name: M47997
exact_source: NIHMS1558781-supplement-4 Figure 4A & 5A
external_details_URL: https://doi.org/10.1158/0008-5472.CAN-19-2961
source_species_code: HS
GEO_id: MSV000084023
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins found in significantly higher abundance in TNBC bone metastasis niche compared to TNBC brain, liver and lung metastatic niches.

description_full:
  We have previously developed methods for enriching tissue samples for their ECM protein content by taking advantage of the relative insolubility of the ECM, and we have used these techniques in conjunction with mass spectrometry-based proteomics to profile the  matrisome,  the complete collection of both core ECM and ECM-associated proteins, in several different cancers. Here we define and compare the ECM components of metastatic niches and how they differ among the specific secondary sites common in TNBC. For this purpose, we use as a model the MDA-MB-231 human TNBC cell line, originally derived from a patient pleural effusion (24), which is capable of metastasizing to the brain, lungs, liver and bone marrow in mouse xenografts. We identify which ECM proteins are commonly elevated at multiple different metastatic sites, and which are preferentially elevated in particular sites. We investigate how these specific ECM proteins, as well as the tumor matrix overall, are differentially produced by the tumor and stromal cells; in this paper, we use  stromal  to include all cells in the tumor that are not tumor cells. These comparisons did not simply identify the most elevated proteins in each tissue, but rather the proteins most significantly different in abundance in one tissue relative to all others. Separate analyses were conducted for tumor-cell-derived (human) and stroma-derived (mouse) proteins. In this study, we performed an unbiased, quantitative mass spectrometric survey of ECM proteins present in MDA-MB-231 breast cancer xenograft metastases to the brain, lungs, liver and bone marrow. This gene set lists the matrisome proteins found in significantly higher abundance in TNBC bone metastasis niche compared to TNBC brain, liver and lung metastatic niches.


systematic_name: M47998
exact_source: NIHMS1558781-supplement-4 Figure 4A & 5A
external_details_URL: https://doi.org/10.1158/0008-5472.CAN-19-2961
source_species_code: HS
GEO_id: MSV000084023
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Tumor cell-derived matrisome proteins found in significantly higher abundance in TNBC brain metastasis niche compared to TNBC bone, liver and lung metastatic niches.

description_full:
  We have previously developed methods for enriching tissue samples for their ECM protein content by taking advantage of the relative insolubility of the ECM, and we have used these techniques in conjunction with mass spectrometry-based proteomics to profile the  matrisome,  the complete collection of both core ECM and ECM-associated proteins, in several different cancers. Here we define and compare the ECM components of metastatic niches and how they differ among the specific secondary sites common in TNBC. For this purpose, we use as a model the MDA-MB-231 human TNBC cell line, originally derived from a patient pleural effusion (24), which is capable of metastasizing to the brain, lungs, liver and bone marrow in mouse xenografts. We identify which ECM proteins are commonly elevated at multiple different metastatic sites, and which are preferentially elevated in particular sites. We investigate how these specific ECM proteins, as well as the tumor matrix overall, are differentially produced by the tumor and stromal cells; in this paper, we use  stromal  to include all cells in the tumor that are not tumor cells. These comparisons did not simply identify the most elevated proteins in each tissue, but rather the proteins most significantly different in abundance in one tissue relative to all others. Separate analyses were conducted for tumor-cell-derived (human) and stroma-derived (mouse) proteins. In this study, we performed an unbiased, quantitative mass spectrometric survey of ECM proteins present in MDA-MB-231 breast cancer xenograft metastases to the brain, lungs, liver and bone marrow. This gene set lists the tumor-cell secreted matrisome proteins found in significantly higher abundance in TNBC brain metastasis niche compared to TNBC bone, liver and lung metastatic niches.


systematic_name: M47999
exact_source: NIHMS1558781-supplement-4 Figure 4A & 5A
external_details_URL: https://doi.org/10.1158/0008-5472.CAN-19-2961
source_species_code: HS
GEO_id: MSV000084023
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins found in significantly higher abundance in TNBC brain metastasis niche compared to TNBC bone, liver and lung metastatic niches.

description_full:
  We have previously developed methods for enriching tissue samples for their ECM protein content by taking advantage of the relative insolubility of the ECM, and we have used these techniques in conjunction with mass spectrometry-based proteomics to profile the  matrisome,  the complete collection of both core ECM and ECM-associated proteins, in several different cancers. Here we define and compare the ECM components of metastatic niches and how they differ among the specific secondary sites common in TNBC. For this purpose, we use as a model the MDA-MB-231 human TNBC cell line, originally derived from a patient pleural effusion (24), which is capable of metastasizing to the brain, lungs, liver and bone marrow in mouse xenografts. We identify which ECM proteins are commonly elevated at multiple different metastatic sites, and which are preferentially elevated in particular sites. We investigate how these specific ECM proteins, as well as the tumor matrix overall, are differentially produced by the tumor and stromal cells; in this paper, we use  stromal  to include all cells in the tumor that are not tumor cells. These comparisons did not simply identify the most elevated proteins in each tissue, but rather the proteins most significantly different in abundance in one tissue relative to all others. Separate analyses were conducted for tumor-cell-derived (human) and stroma-derived (mouse) proteins. In this study, we performed an unbiased, quantitative mass spectrometric survey of ECM proteins present in MDA-MB-231 breast cancer xenograft metastases to the brain, lungs, liver and bone marrow. This gene set lists the matrisome proteins found in significantly higher abundance in TNBC brain metastasis niche compared to TNBC bone, liver and lung metastatic niches.


systematic_name: M48000
exact_source: NIHMS1558781-supplement-4 Figure 4A & 5A
external_details_URL: https://doi.org/10.1158/0008-5472.CAN-19-2961
source_species_code: HS
GEO_id: MSV000084023
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Tumor cell-derived matrisome proteins found in significantly higher abundance in TNBC lung metastasis niche compared to TNBC brain, liver and bone metastatic niches.

description_full:
  We have previously developed methods for enriching tissue samples for their ECM protein content by taking advantage of the relative insolubility of the ECM, and we have used these techniques in conjunction with mass spectrometry-based proteomics to profile the  matrisome,  the complete collection of both core ECM and ECM-associated proteins, in several different cancers. Here we define and compare the ECM components of metastatic niches and how they differ among the specific secondary sites common in TNBC. For this purpose, we use as a model the MDA-MB-231 human TNBC cell line, originally derived from a patient pleural effusion (24), which is capable of metastasizing to the brain, lungs, liver and bone marrow in mouse xenografts. We identify which ECM proteins are commonly elevated at multiple different metastatic sites, and which are preferentially elevated in particular sites. We investigate how these specific ECM proteins, as well as the tumor matrix overall, are differentially produced by the tumor and stromal cells; in this paper, we use  stromal  to include all cells in the tumor that are not tumor cells. These comparisons did not simply identify the most elevated proteins in each tissue, but rather the proteins most significantly different in abundance in one tissue relative to all others. Separate analyses were conducted for tumor-cell-derived (human) and stroma-derived (mouse) proteins. In this study, we performed an unbiased, quantitative mass spectrometric survey of ECM proteins present in MDA-MB-231 breast cancer xenograft metastases to the brain, lungs, liver and bone marrow. This gene set lists the tumor-cell secreted matrisome proteins found in significantly higher abundance in TNBC lung metastasis niche compared to TNBC brain, liver and bone metastatic niches.


systematic_name: M48001
exact_source: NIHMS1558781-supplement-4 Figure 4A & 5A
external_details_URL: https://doi.org/10.1158/0008-5472.CAN-19-2961
source_species_code: HS
GEO_id: MSV000084023
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins found in significantly higher abundance in TNBC lung metastasis niche compared to TNBC bone, liver and brain metastatic niches.

description_full:
  We have previously developed methods for enriching tissue samples for their ECM protein content by taking advantage of the relative insolubility of the ECM, and we have used these techniques in conjunction with mass spectrometry-based proteomics to profile the  matrisome,  the complete collection of both core ECM and ECM-associated proteins, in several different cancers. Here we define and compare the ECM components of metastatic niches and how they differ among the specific secondary sites common in TNBC. For this purpose, we use as a model the MDA-MB-231 human TNBC cell line, originally derived from a patient pleural effusion (24), which is capable of metastasizing to the brain, lungs, liver and bone marrow in mouse xenografts. We identify which ECM proteins are commonly elevated at multiple different metastatic sites, and which are preferentially elevated in particular sites. We investigate how these specific ECM proteins, as well as the tumor matrix overall, are differentially produced by the tumor and stromal cells; in this paper, we use  stromal  to include all cells in the tumor that are not tumor cells. These comparisons did not simply identify the most elevated proteins in each tissue, but rather the proteins most significantly different in abundance in one tissue relative to all others. Separate analyses were conducted for tumor-cell-derived (human) and stroma-derived (mouse) proteins. In this study, we performed an unbiased, quantitative mass spectrometric survey of ECM proteins present in MDA-MB-231 breast cancer xenograft metastases to the brain, lungs, liver and bone marrow. This gene set lists the matrisome proteins found in significantly higher abundance in TNBC lung metastasis niche compared to TNBC bone, liver and brain metastatic niches.


systematic_name: M48002
exact_source: NIHMS1558781-supplement-4 Figure 4A & 5A
external_details_URL: https://doi.org/10.1158/0008-5472.CAN-19-2961
source_species_code: HS
GEO_id: MSV000084023
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins found in significantly higher abundance in TNBC liver metastasis niche compared to TNBC brain, lung and bone metastatic niches.

description_full:
  We have previously developed methods for enriching tissue samples for their ECM protein content by taking advantage of the relative insolubility of the ECM, and we have used these techniques in conjunction with mass spectrometry-based proteomics to profile the  matrisome,  the complete collection of both core ECM and ECM-associated proteins, in several different cancers. Here we define and compare the ECM components of metastatic niches and how they differ among the specific secondary sites common in TNBC. For this purpose, we use as a model the MDA-MB-231 human TNBC cell line, originally derived from a patient pleural effusion (24), which is capable of metastasizing to the brain, lungs, liver and bone marrow in mouse xenografts. We identify which ECM proteins are commonly elevated at multiple different metastatic sites, and which are preferentially elevated in particular sites. We investigate how these specific ECM proteins, as well as the tumor matrix overall, are differentially produced by the tumor and stromal cells; in this paper, we use  stromal  to include all cells in the tumor that are not tumor cells. These comparisons did not simply identify the most elevated proteins in each tissue, but rather the proteins most significantly different in abundance in one tissue relative to all others. Separate analyses were conducted for tumor-cell-derived (human) and stroma-derived (mouse) proteins. In this study, we performed an unbiased, quantitative mass spectrometric survey of ECM proteins present in MDA-MB-231 breast cancer xenograft metastases to the brain, lungs, liver and bone marrow. This gene set lists the matrisome proteins found in significantly higher abundance in TNBC liver metastasis niche compared to TNBC brain, lung and bone metastatic niches.


systematic_name: M48003
exact_source: NIHMS1558781-supplement-4 Figure 4B & 5B
external_details_URL: https://doi.org/10.1158/0008-5472.CAN-19-2961
source_species_code: HS
GEO_id: MSV000084023
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Tumor cell-derived matrisome proteins found in significantly higher abundance in TNBC brain, bone, liver and lung metastatases compared to normal samples.

description_full:
  We have previously developed methods for enriching tissue samples for their ECM protein content by taking advantage of the relative insolubility of the ECM, and we have used these techniques in conjunction with mass spectrometry-based proteomics to profile the  matrisome,  the complete collection of both core ECM and ECM-associated proteins, in several different cancers. Here we define and compare the ECM components of metastatic niches and how they differ among the specific secondary sites common in TNBC. For this purpose, we use as a model the MDA-MB-231 human TNBC cell line, originally derived from a patient pleural effusion (24), which is capable of metastasizing to the brain, lungs, liver and bone marrow in mouse xenografts. We identify which ECM proteins are commonly elevated at multiple different metastatic sites, and which are preferentially elevated in particular sites. We investigate how these specific ECM proteins, as well as the tumor matrix overall, are differentially produced by the tumor and stromal cells; in this paper, we use  stromal  to include all cells in the tumor that are not tumor cells. These comparisons did not simply identify the most elevated proteins in each tissue, but rather the proteins most significantly different in abundance in one tissue relative to all others. Separate analyses were conducted for tumor-cell-derived (human) and stroma-derived (mouse) proteins. In this study, we performed an unbiased, quantitative mass spectrometric survey of ECM proteins present in MDA-MB-231 breast cancer xenograft metastases to the brain, lungs, liver and bone marrow. This gene set lists the tumor-cell secreted matrisome proteins found in significantly higher abundance in TNBC brain, bone, liver and lung metastatases compared to normal samples.


systematic_name: M48004
exact_source: NIHMS1558781-supplement-4 Figure 4B & 5B
external_details_URL: https://doi.org/10.1158/0008-5472.CAN-19-2961
source_species_code: HS
GEO_id: MSV000084023
contributor: Alexandra Naba
contrib_organization: University of Illinois Chicago
description_brief:
  Matrisome proteins found in significantly higher abundance in TNBC brain, bone, liver and lung metastatases compared to normal samples.

description_full:
  We have previously developed methods for enriching tissue samples for their ECM protein content by taking advantage of the relative insolubility of the ECM, and we have used these techniques in conjunction with mass spectrometry-based proteomics to profile the  matrisome,  the complete collection of both core ECM and ECM-associated proteins, in several different cancers. Here we define and compare the ECM components of metastatic niches and how they differ among the specific secondary sites common in TNBC. For this purpose, we use as a model the MDA-MB-231 human TNBC cell line, originally derived from a patient pleural effusion (24), which is capable of metastasizing to the brain, lungs, liver and bone marrow in mouse xenografts. We identify which ECM proteins are commonly elevated at multiple different metastatic sites, and which are preferentially elevated in particular sites. We investigate how these specific ECM proteins, as well as the tumor matrix overall, are differentially produced by the tumor and stromal cells; in this paper, we use  stromal  to include all cells in the tumor that are not tumor cells. These comparisons did not simply identify the most elevated proteins in each tissue, but rather the proteins most significantly different in abundance in one tissue relative to all others. Separate analyses were conducted for tumor-cell-derived (human) and stroma-derived (mouse) proteins. In this study, we performed an unbiased, quantitative mass spectrometric survey of ECM proteins present in MDA-MB-231 breast cancer xenograft metastases to the brain, lungs, liver and bone marrow. This gene set lists the matrisome proteins found in significantly higher abundance in TNBC brain, bone, liver and lung metastatases compared to normal samples.


description_brief: Genes encoding collagen proteins
systematic_name: M3005
external_details_URL: http://matrisome.org
source_species_code: HS
contributor: Alexandra Naba
contrib_organization: Massachusetts Institute of Technology
description_full:
  One hallmark of ECM proteins is their domain-based structure. Exploiting this characteristic, we established a list of diagnostic InterPro domains commonly found in ECM proteins. This domain list was used to screen the UniProt protein database. We know that some of the domains used to select positively for ECM proteins are also found in transmembrane receptors and proteins involved in cell adhesion (growth factor receptors, integrins, etc) that do not belong to the ECM. These families of proteins also display a subset of specific domains and transmembrane domains incompatible with definition as “extracellular matrix” proteins. Therefore, a second step comprised a negative selection using another set of domains and a transmembrane domain prediction. Manual curation of the matrisome lists also allowed us to add a very few known ECM proteins that do not contain any known domains. Protein-centric predictions were then converted to gene-centric lists. Finally, knowledge-based annotation of these gene lists allowed us to define subcategories within the core matrisome; namely, ECM glycoproteins, collagens, and proteoglycans.  We also  defined separate lists of domains commonly found in 1) ECM-affiliated proteins (proteins that share either some architectural similarities with ECM proteins or that are known to be associated with ECM proteins; 2) ECM regulators: ECM-remodeling enzymes, crosslinkers, proteases, regulators etc.; 3) secreted factors, many of which are known to bind to ECM and others that may. As for the core matrisome list, we also defined lists of domains that excluded mis-assigned proteins from these categories. Using similar bioinformatic pipelines as for the core matrisome, we defined three categories of “matrisome-associated” proteins: ECM-affiliated proteins, ECM regulators, and secreted factors.


systematic_name: M5884
external_details_URL: http://matrisome.org
source_species_code: HS
contributor: Alexandra Naba
contrib_organization: Massachusetts Institute of Technology
description_brief:
  Ensemble of genes encoding core extracellular matrix including ECM glycoproteins, collagens and proteoglycans

description_full:
[cell repeats an earlier one in this file: 1838 characters]


systematic_name: M5885
external_details_URL: http://matrisome.org
source_species_code: HS
contributor: Alexandra Naba
contrib_organization: Massachusetts Institute of Technology
description_brief:
  Ensemble of genes encoding ECM-associated proteins including ECM-affilaited proteins, ECM regulators and secreted factors

description_full:
[cell repeats an earlier one in this file: 1838 characters]


description_brief: Adhesion and Diapedesis of Granulocytes
systematic_name: M5467
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_granulocytesPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Cell adhesion is a fundamental feature of multicellular organisms including their defense mechanisms. In the later case in mammals, leukocytes play central role. They bind bacteria, parasites, viruses, tumor cells etc. Furthermore, their interactions with the endothelium are of special importance. During an inflammation or immune reaction, specialized leukocytes (eosinophilic granulocytes) adhere to and pass through the endothelium of the blood vessels and the underlying matrix. The reaction passes through the following steps: 1. Rolling (the flow of cells is slowed down by first making contacts to the endothelium via P-, E-, and L-selectins and their receptors); 2. Adhesion (After activation of leukocyte integrins, firm contacts are established between them and endothelium molecules of the Ig superfamily - LFA-1, Mac-1, VLA-4 etc.); 3. Flattening of the cells and diapedesis (Adhering leukocytes crawl to an intercellular junction of the endothelium and then transmigrate to or even through the intercellular matrix. This is mediated by a homophilic interactions of PECAM and CD31.


description_brief: Adhesion and Diapedesis of Lymphocytes
systematic_name: M1469
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_lymPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Cell adhesion is a fundamental feature of multicellular organisms including their defense mechanisms. In the later case in mammals, leukocytes play central role. They bind bacteria, parasites, viruses, tumor cells etc. Furthermore, their interactions with the endothelium are of special importance. Generally, lymphocyte adhesion and passage from the bloodstream to the lymphatic system occurs in the high endothelial venules of the lymphnodes. This way the lymphocytes can communicate with each other in the lymphatic system and search for foreign compounds after their recirculation to the bloodstream, this fulfilling their role in the immune system. The reaction passes through the following steps: 1. Rolling (the flow of cells is slowed down by first making contacts to the endothelium via P-, E-, and L-selectins and their receptors); 2. Adhesion (After activation of leukocyte integrins, firm contacts are established between them and endothelium molecules of the Ig superfamily - LFA-1, Mac-1, VLA-4 etc.); 3. Flatteningof the cells and diapedesis (Adhering leukocytes crawl to an intercellular junction of the endothelium and then transmigrate to or even through the intercellular matrix. This is mediated by a homophilic interactions of PECAM and CD31.


description_brief: B Lymphocyte Cell Surface Molecules
systematic_name: M1473
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_blymphocytePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  B cells must communicate with their environment to participate in the immune system as the source of antigen-specific immunoglobulins. Cell surface proteins on B cells receive signals from the exterior, adhere to other cells, and transmit signals to other cells. Antigen recognized by a B cell's immunoglobulin is presented in MHC Class II to T cells during B cell activation. Cell surface immunoglobulins are a key to B cell function, assisting in the response of B cells to specific antigen recognized by that cell's immunoglobulin. CD54 (ICAM-1) is an adhesion molecule involved in the binding of B cells to other cell types and LFA-1 is an integrin adhesion protein with two subunits that binds to ICAM. CD35 and CD21 are receptors for complement factors that stimulate the B cell response when complement is activated. CD80 and CD40 bind to T cell proteins (CD28 and CD40L, respectively) to provide costimulatory signals in the B cell-T cell interaction required for B cell activation. CD45 is a protein tyrosine phosphatase that regulates activation of B cells and T cells through dephosphorylation of signaling factors. CD32 is a receptor for IgG Fc, and is also called FcgammaRII. The number of proteins on the surface of B cell proteins indicates the complexity of regulation of B cell activation.


description_brief: CARM1 and Regulation of the Estrogen Receptor
systematic_name: M2499
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_carm-erPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Several forms of post-translational modification regulate protein activities. Recently, protein methylation by CARM1 (coactivator-associated arginine methyltransferase 1) has been observed to play a key role in transcriptional regulation. CARM1 associates with the p160 class of transcriptional coactivators involved in gene activation by steroid hormone family receptors. CARM1 also interacts with CBP/p300 transcriptional coactivators involved in gene activation by a large variety of transcription factors, including steroid hormone receptors and CEBP. One target of CARM1 is the core histones H3 and H4, which are also targets of the histone acetylase activity of CBP/p300 coactivators. Recruitment of CARM1 to the promoter region by binding to coactivators increases histone methylation and makes promoter regions more accessible for transcription. Another target of CARM1 methylation is a coactivator it interacts with, CBP. Methylation of CBP by CARM1 blocks CBP from acting as a coactivator for CREB and redirects the limited CBP pool in the cell to be available for steroid hormone receptors. Other forms of post-translational protein modification such as phosphorylation are reversible in nature, but as of yet a protein demethylase is not known. The methylation activity of CARM1 modulates the activity of specific transcriptional regulators. CARM1 acts as a coactivator for the myogenic transcription factor Mef2c, and is necessary for normal muscle cell differentiation. The estrogen receptor is another transcription factor that uses CARM1 as one of several coactivators, acting synergistically with CBP through the Grip1 member of the p160 family of coactivators. The interaction of estrogen receptor with various ligand-dependent coactivators may produce the tissue selective response of some estrogen receptor ligands like tamoxifen.


description_brief: Cells and Molecules involved in local acute inflammatory response
systematic_name: M3952
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_LairPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Inflammation has several distinct components, including the localized response at the site of tissue injury or infection. Tissue injury stimulates the release of inflammatory signaling molecules such as bradykinin. Bacterial infection stimulates an immune response in several ways. Bacteria that are phagocytosed can activate macrophages, causing the release of inflammatory cytokines such as IL-1, TNF, and IL-6. Bacteria can also activate the complement cascade through either the antibody-mediated pathway (classical pathway) or the alternative complement pathway. In extravascular tissues, cells that respond to infection or injury include macrophages and mast cells. Macrophages and other immune cells secrete chemokines that recruit leukocytes from the circulation to the site of inflammation. Mast cells release histamine, prostaglandins, and leukotrienes that act as chemokines, increase vascular permeability, and act on the vascular endothelium to increase tissue recruitment of leukocytes. Chemokines can recruit leukocytes or lymphocytes out of the blood stream into tissues and make blood vessels more permeable. Leukocytes are activated by inflammatory signals to express adhesion molecules that cause them to interact with the vascular endothelium, penetrate the endothelial wall and migrate into the extracellular space of tissues. The combined response of immune cells and signaling molecules at the site of inflammation induces swelling, activation of immune cells, and clearance of potential infectious agents. Chronic inflammation can however also lead to tissue damage in conditions such as arthritis, in which anti-inflammatory drugs act on various steps in inflammation to prevent disease.


description_brief: Control of Gene Expression by Vitamin D Receptor
systematic_name: M13404
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_vdrPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The vitamin D receptor, VDR is the mediator of all genomic actions of vitamin D3 and its analogs. It belongs to a family of ligand induced transcription factors, nuclear receptors (NRs). Vitamin D3 is the main regulator of calcium homeostasis and is critical in bone formation. It is also involved in controlling cellular growth, differentiation and apoptosis, which makes synthetic vitamin D3 analogues interesting for therapy of such diseases as cancer and psoriasis. NRs are comprised of: an amino-terminal activation function domain AF-1; the DNA-binding domain; a hinge region; and a carboxy-terminal ligand-binding domain containing a second activation function, AF-2. VDR acts primarily as a heterodimer with the retinoid X receptor (RXR) on vitamin D response elements (VDREs). It interacts with the transcription machinery and nuclear receptor coactivators or corepressors to regulate target gene activity. NRs coregulators can be divided into 3 major classes: 1)ATP-dependent chromatin remodeling complexes that are involved in the location and association of nucleosomes with DNA; 2) Enzymes that catalyze modifications of histone tails to regulate histone-histone and histone-DNA interactions 3) General transcription factors adaptors that bridge the functions between regulators and basal transcription factors. A novel multifunctional ATP-dependent chromatin remodeling complex c WINAC directly interacts with the vitamin D receptor. It contains BRG1 or hBRM as ATPase subunits as all SWI/SNF complexes do, but it also has subunits associated with DNA replication (TopoII_ and CAF-1p150) and transcript elongation through nucleosomes (FACTP140) not found before in SWI/SNF complexes. WINAC also contains the Williams syndrome transcription factor (WSTF). WSTF appears to function as a platform protein for the assembly of components in WINAC, and it interacts directly with the vitamin D receptor in a ligand-independent manner. WINAC and vitamin Dreceptor are targeted to vitamin D responsive promoters in the absence of ligand to both positively and negatively regulated genes. WINAC may rearrange the nucleosome array around the positive and negative VDREs, thereby facilitating the coregulatory complexes access for further transcription control. Upon ligand binding, two HAT complexes, p160/CBP and TRRAP/PCAF, coactivate the NR function. The p160 proteins (SRC protein family) interact directly with an NR activation surface AF2 and serve as platforms for the recruitment of histone-modifying enzymes, including CBP/p300 and methyltransferases. The SRC/p160 family members SRC-1 and p/CIP, as well as CBP and p300 contain intrinsic histone acetyltransferase activity(HAT). Both the HAT activity and the histone methyltransferase activity may cooperate in histone modification and facilitate nucleosome remodeling and recruitment of transcriptional machinery. A third group of coactivators is represented by thyroid receptor-associated proteins (TRAP)/vitamin D receptor-interacting proteins (DRIP). This complex may play a role by directly contacting the basal transcriptional machinery. As the VDR/RXR heterodimer also represses transcription in a ligand-dependent manner through negative VDRE (nVDRE), a number of corepressor proteins such as NCoR and ALIEN may also be recruited to the surface of the receptor. They, too function as platforms but serve to recruit enzymes such as histone deacetylases. WINAC association with VDR facilitates targeting of a putative corepressor complex to the nVDRE


description_brief: Downregulated of MTA-3 in ER-negative Breast Tumors
systematic_name: M225
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_mta3Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Approximately 30% of breast carcinomas lack ER expression. Presumably, these breast cancers become estrogen independent through genetic alterations that bypass the requirement for ER-dependent stimulation of cell proliferation. As such estrogen receptor is a key regulator of proliferation and differentiation in mammary epithelia and represents a crucial prognostic indicator and therapeutic target in breast cancer. Mechanistically, estrogen receptor induces changes in gene expression through direct gene activation of a number of genes (cathepsin D, HSP27 (heat shock protein 27,000 kDa, aldolase A, dehydrogenase, alpha-tubulin, and glyceraldehyde-3-phosphat, Pdzk1, Greb ets) and also through the biological functions of target loci. The product of human MTA3 has been identified as an estrogen-dependent component of the Mi-2/NuRD transcriptional corepressor in breast epithelial cells and demonstrate that MTA3 constitutes a key component of an estrogen-dependent pathway regulating growth and differentiation. The absence of estrogen receptor or of MTA3 leads to aberrant expression of the transcriptional repressor Snail, a master regulator of epithelial to mesenchymal transitions. Aberrant Snail expression results in loss of expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. MTA3 is the mechanistic link between estrogen receptor status and invasive growth of breast cancers.


description_brief: Gamma-aminobutyric Acid Receptor Life Cycle
systematic_name: M477
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_gabaPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Gamma-amino butyric acid (GABA) is an inhibitory neurotransmitter that acts at synapses through binding to ligand-gated ion channels, the GABA receptors. Clustering of the GABA-A receptor chloride channel alters receptor pharmacology on the cell surface and reduced clustering of the GABA receptor is associated with anxiety. GABA-A interacts with several proteins that modulate its clustering, endocytosis, and recycling or degradation. Plic-1 is a ubiquitin-like protein that binds to GABA-A receptors and causes them to accumulate at inhibitory synapses. Gephyrin interacts with the cytoplasmic domain of GABA-A, and with microtubules, bringing receptors together in plasma microdomains. Curiously, Gephyrin appears to be a bifunctional protein, with a domain involved in molybdenum metabolism. Another protein interacting with the GABA-A receptor is GABARAP, a microtubule-associated protein. Anchoring of the GABA-A receptor to GABARAP helps to cluster the receptor at the synaptic termini and to mediate fast synaptic transmission. GABARAP may mediate interaction of gephyrin with the GABA-A receptor and gephyrin may stabilize clusters by forming multimeric structures. GABARAP and gephyrin may play more of a role in receptor sorting and transport to the cell surface than in anchoring to the cytoplasm, since at inhibitory synapses GABARAP appears to associated with transport vesicles rather than the cell surface. The association of GABARAP with NSF (N-ethyl maleimide sensitive factor), a protein involved in intracellular vesicle transport, supports this hypothesis.


description_brief: Map Kinase Inactivation of SMRT Corepressor
systematic_name: M18837
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_egfr_smrtePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Corepressors are coregulators that interact with transcriptional silencers in a variety of pathways such as cell proliferation, differentiation and apoptosis. Abnormal corepressor-silencer interactions have been implicated in a variety of human disease pathways including several types of leukemia. The regulation of the SMRT corepressor via the p38 and Mek-1 Kinase pathway is shown in this diagram. The EFG receptor represents one mechanism by which SMRT function is inhibited by the tyrosine kinase signaling pathway. The MEKK1 and p38 pathways are activated by EGF resulting in cross-regulation of SMRT. The induction of SMRT phosphorylation by each pathway is shown, causing SMRT to unbind from the transcription factor complexes represented by RXR, RAR, T3R and PLZF.


description_brief: Monocyte and its Surface Molecules
systematic_name: M4956
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_monocytePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Monocytes are a class of phagocytes involved in non-specific immune defense that develop into macrophages. In plasma, monocytes ingest and destroy bacteria, and can form macrophages when they enter the extracellular space in tissues. In addition to the immune protection that monocytes provide, they may contribute to disease states such as arthritis and heart disease through an aberrant immune response. As with other immune cells, the immune function and differentiation of monocytes rely on communication with other cells through cell surface proteins. Cell surface proteins are involved in both interaction and adhesion with other cells and in transducing signals into the cellular interior. The LFA-1 integrin (Leukocyte function-associated molecule 1) is composed of two subunits, CD11a and CD18 and is involved in monocytes adhesion with ICAM-1 endothelial cells. Mac-1 is composed of the subunits CD11b and CD18 and is induced during inflammation as well. PECAM-1 mediates the migration of monocytes and other immune cells into inflamed tissues through interaction with vascular endothelial cells. CD44 interaction of leukocytes with hyaluronan in the extracellular matrix is induced by inflammation. VLA-4 is another integrin expressed on lymphocytes that plays a role in adhesion through interaction with its adhesion partner on endothelial cells, VCAM-1.


systematic_name: M6907
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_rarrxrPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_brief:
  Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription in carcinoma cells

description_full:
  RXR and RAR are nuclear receptors that bind either all trans retinoic (tRA) or 9cis retinoic acid (9cisRA). In the absence of ligand corepressors with histone deacetylase activity are bound to the RAR/RXR hetrodimer and suppress transcription. Once they bind retinoic acid a conformational change in the receptors cause the dissociation of the corepressors and the binding of coactivators with histone acetylase activity (1). Following ligand binding by the hetrodimer the receptors and proteins in the basal transcription machinery (like TBP and TAF135) are degraded by the proteasome (2).


description_brief: Nuclear Receptors in Lipid Metabolism and Toxicity
systematic_name: M16393
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_nuclearRsPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Nuclear receptors are transcription factors that are activated upon binding to its ligands. Initially, they had been classified as classic endocrine nuclear hormone receptors and orphan receptors. However, further studies have led to the identification of lipid ligands for some of these adopted orphan receptors, which are responsible for lipid metabolism, storage or elimination. One of the characteristics of these receptors is that they act by forming heterodimers with retinoid X receptor (RXR). The receptors include peroxisome proliferators-Activated receptors (PPARs) for fatty acids, liver X receptor (LCR) for oxysterols, Farnesoid X receptors (FXR) for bile acids and steroid xenobiotic receptor/X receptor (SXR/PXR or Nsil2) for xenobiotics. Other orphan receptors also require RXR for its functions are vitamin D receptor (VDR) for vitamin D and retinoic acid receptor (RAR) for retinoid acids, although these receptors are not involved in lipid metabolism. Upon binding to various ligands, three classes of proteins are synthesized including lipid binding proteins, the ATP-binding cassette (ABC) transporters and cytochrome P450 member proteins which catalyzes lipid anabolism, metabolism and elimination. In addition to lipid metabolism, some members of the cytochrome P450 family genes are responsible for activation of procarcinogens, detoxification of environmental toxins and metabolism of drugs and xenobiotics. In particular, CAR, Nsil2 and recently identified VDR are important in up-regulation of these cytochromes. Of all the human cytochrome P450 genes, only a few CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 account for most toxicity effects, specifically CYP3A is responsible for clearing approximately half of the clinically prescribed drugs. For instance, acetaminophen, one of the most commonly used drug, is toxic in high doses due to the activation of CAR and the drugs subsequentconversion to acetyl-p-benzoquinone imine (NAPQI) by CYP1A2, CYP2E1 and CYP3A.


description_brief: Role of Ran in mitotic spindle regulation
systematic_name: M17370
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ranMSPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  One of the central features of mitotic cell division is the formation of the spindle that segregates chromosomes into each daughter cell. Chromosomes are not just passengers along for a ride with the spindle, but active participants in the nucleation and stabilization of spindle microtubules in their near vicinity. The ras-like GTPase Ran that regulates nucleocytoplasmic transport through the nuclear pore complex (NPC) during interphase also regulates the formation of the mitotic spindle. Ran plays a similar role in each of these processes, regulating downstream signaling pathways in a differential manner based on whether GDP or GTP is bound. Like other GTPases, the inherent GTPase activity of Ran is regulated by GTPase activating proteins (GAPs) and by exchange factors. An exchange factor that stimulates nucleotide exchange by the Ran GTPase is RCC1, which binds to chromatin in both interphase and mitosis. While RCC1 helps RAN drive transport between the nucleus and cytoplasm during interphase, the localization of RCC1 on chromatin during mitosis localizes Ran-GTP near chromosomes, localizing microtubule formation in these regions. Ran-BP1 and Ran-GAP1 stimulate GTP hydrolysis by Ran, converting it back to Ran-GDP further away from chromosomes. Aster promoting activities (APA) and the importin-alpha and importin-beta proteins involved with Ran in nucleocytoplasmic transport are also involved in mitotic spindle formation. Aster promoting activities stabilize microtubules during spindle formation, but binding of importins to APA neutralizes their activity in forming microtubules. The importins bind to APA when far from the chromosomes, where Ran-GDP predominates, but Ran-GTP near chromosomes causes importins to release APA factors including Tpx2 and NuMa, allowing them to stimulate microtubule formation. Tpx2 interacts with the microtubule motor protein Xklp2 and also activates the Aurora A mitotic kinase, required for spindle formation. In addition to regulating spindle formation, Ran may also help reform the nuclear envelope after cell division and may use a similar mechanism to regulate other cellular processes.


description_brief: Telomeres, Telomerase, Cellular Aging, and Immortality
systematic_name: M10401
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_telPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Telomeres, which define the ends of chromosomes, consist of short, tandemly repeated DNA sequences loosely conserved in eukaryotes. Telomerase is a ribonucleoprotein complex ( we only show a few of the components in this illustration) which in vitro recognizes a single-stranded G-rich telomere primer and adds multiple telomeric repeats to its 3-prime end by using an RNA template. Telomerase may also have a role in de novo formation of telomeres. Telomerase has been identified in many cultured cell lines and actively dividing cell types. The active reverse transcriptase component has been identified in teh TERT protein. The presence of this factor determines the availability of the telomerase function. The TERT protein has a high turnover rate and its expression is regulated by factors that promote growth (c-MYC, v-k-ras, Bcl-2 and E6) and inhibiting factors (RB and p53) that promote cell death or that block cell division. It appears that the regulation of active telomerase has many levels and can be inhibited by TEP1 not releasing TERT or by TRF1 which binds the end repeats and prevents access to the chromosome ends. Additional modulation is due to phosphorlyation by PKC and AKT or dephophorylation by PP2A. Wilke et al found that a case of human alpha-thalassemia was caused by a truncation of chromosome 16 that had been healed by the addition of telomeric repeats (TTAGGG)n. Human telomeres consist of many kilobases of (TTAGGG)n together with various associated proteins. Small amounts of these terminal sequences are lost from the tips of the chromosomes during each S phase because of incomplete DNA replication, but de novo addition of TTAGGG repeats by the enzyme telomerase compensates for this loss. Many human cells progressively lose terminal bases with each cell division, a loss that correlates with the apparent absence of telomerase in these cells. There has been considerable interest in the possible relationship between human telomeres and cellular senescence and immortalization. This interest includes the question of a role in the malignant process and the question of the use of telomerase inhibitors as anti-tumor drugs.


description_brief: SARS Coronavirus Protease
systematic_name: M5374
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_SARSpathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Severe Acute Respiratory Syndrome (SARS) has affected thousands of individuals, causing fever, and pneumonia with a mortality rate estimated at 10-18%. A novel coronavirus has been identified as the cause agent and its genome has been sequenced. Human coronaviruses cause mild respiratory illness and accounts for about a third of all cases of the common cold. The enveloped SARS virus contains a large + strand RNA genome, approximately 30,000 nucleotides. Examination of the SARS coronavirus sequences reveals that rep gene covers over 20,000 nucleotides and encodes two overlapping polyproteins cleaved by viral proteases into smaller protein products. Translation of the longer polyprotein encoded by the rep gene requires a ribosomal frameshift. Other viral genes are predicted to encode the transmembrane spike protein S involved in viral fusion with host cells, the envelope protein E, the membrane protein M and the nucleocapsid protein N that binds to the RNA genome as well as several additional open reading frames with unknown functions. Viral entry into the cell is followed by translation of the viral rep gene, which codes for a viral protease within the polyprotein, Mpro or 3CLpro. The SARS 3CLpro has also been verified in vitro to cleave after the Gln residue at Leu-Gln-(Ser, Ala, Gly),. Polypeptides released from the polyproteins by the main viral protease Mpro or 3CLpro include the viral polymerase and a protease. Both products are essential for viral replication and transcription. Structural crystals of a porcine coronavirus protease with a transition state inhibitor suggest that inhibitors of the distantly related rhinovirus protease like the drug AG7088 may be modified to produce drugs that block the SARS protease and viral replication. Blocking entry of the SARS virus into cells, involving recognition of cellular receptors by the S spike protein, may provide another strategy for the development of drugs to treat SARS.


description_brief: ChREBP regulation by carbohydrates and cAMP
systematic_name: M22004
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_chrebpPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Liver is the major site for carbohydrate metabolism (glycolysis and glycogen synthesis) and triglyceride synthesis (lipogenesis). While insulin was long thought to be the major regulator of hepatic gene expression, emerging evidence show that nutrients, in particular, glucose and fatty acids, are also able to regulate hepatic genes. This diagram illustrates how glucose metabolite, rather than glucose itself, contributes to the coordinated regulation of carbohydrate and lipid homeostasis in liver through phosphorylation-dependent regulation of ChREBP (carbohydrate responsive element binding protein). ChREBP is a basic helix-loop helix/leucine zipper (bHLH/LZ) transcription factor, shuttling between the cytoplasm and nucleus in a glucose-responsive manner in hepatocytes. When serum glucose is elevated, glucose transporter (GLUT2) and glucokinase (GCK) allow for rapid uptake and equilibration of intracellular glucose levels. This flux of glucose promotes, via the hexose monophosphate shunt pathway (HMP Shunt), the formation of xylulose-5-phosphate (Xu-5-P), which activates protein phosphatase 2A (PP2A) to dephosphorylate ChREBP (Ser196) and promote its nuclear localization. PP2A further dephosphorylates ChREBP in the nucleus, allowing it to dimerize with the bHLH/LZ transcription factor Max-like protein X (MLX) and activate transcription of a number of glycolytic and lipogenic genes containing a ChoRE, such as liver-type pyruvate kinase (L-PK), acetyl-CoA carboxylase 1 (ACACA), and fatty acid synthase (FASN). Upon starvation or high-fat feeding, intrahepatic levels of cAMP and AMP are elevated to activate protein kinase A (PKA) and AMP-dependent protein kinase (AMPK), respectively. PKA-mediated phosphorylation of Thr666 and Ser626 inhibits the DNA binding capacity of ChREBP; so does AMPK-mediated modification of Ser568. PKA-dependent phosphorylation of Ser196 promotes interaction with 14-3-3 and thus sequesters ChREBP in the cytosol. In summary, the phosphorylated form of ChREBP is rendered inactive due to its diminished DNA binding capacity and subcellular compartmentalization. Glucose metabolism triggers dephosphorylation of ChREBP, allowing it to enter the nucleus and activate the transcription of both glycolytic and lipogenic gene expression in liver. The fact that ChREBP/ mice are intolerant to glucose and insulin resistant suggests that ChREBP may also play a role in the pathogenesis of type 2 diabetes.


description_brief: N-Glycan biosynthesis
systematic_name: M11079
exact_source: hsa00510
external_details_URL: http://www.genome.jp/pathway/hsa00510
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  N-glycans or asparagine-linked glycans are major constituents of glycoproteins in eukaryotes. N-glycans are covalently attached to asparagine with the consensus sequence of Asn-X-Ser/Thr by an N-glycosidic bond, GlcNAc b1- Asn. Biosynthesis of N-glycans begins on the cytoplasmic face of the ER membrane with the transferase reaction of UDP-GlcNAc and the lipid-like precursor P-Dol (dolichol phosphate) to generate GlcNAc a1- PP-Dol. After sequential addition of monosaccharides by ALG glycosyltransferases, the N-glycan precursor is attached by the OST (oligosaccharyltransferase) complex to the polypeptide chain that is being synthesized and translocated through the ER membrane. The protein-bound N-glycan precursor is subsequently trimmed, extended, and modified in the ER and Golgi by a complex series of reactions catalyzed by membrane-bound glycosidases and glycosyltransferases. N-glycans thus synthesized are classified into three types: high-mannose type, complex type, and hybrid type. Defects in N-glycan biosynthesis lead to a variety of human diseases known as congenital disorders of glycosylation.


description_brief: O-Glycan biosynthesis
systematic_name: M6929
exact_source: hsa00512
external_details_URL: http://www.genome.jp/pathway/hsa00512
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  O-glycans are a class of glycans that modify serine or threonine residues of proteins. Biosynthesis of O-glycans starts from the transfer of N-acetylgalactosamine (GalNAc) to serine or threonine. The first GalNAc may be extended with sugars including galactose, N-acetylglucosamine, fucose, or sialic acid, but not mannose, glucose, or xylose. Depending on the sugars added, there are four common O-glycan core structures, cores 1 through 4, and an additional four, cores 5 though 8. Mucins are highly O-glycosylated glycoproteins ubiquitous in mucous secretions on cell surfaces and in body fluids. Mucin O-glycans can be branched, and many sugars or groups of sugars are antigenic. Important modifications of mucin O-glycans include O-acetylation of sialic acid and O-sulfation of galactose and N-acetylglucosamine.


description_brief: Glycosylphosphatidylinositol(GPI)-anchor biosynthesis
systematic_name: M13265
exact_source: hsa00563
external_details_URL: http://www.genome.jp/pathway/hsa00563
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Cell surface proteins can be attached to the cell membrane via the glycolipid structure called glycosylphosphatidylinositol (GPI) anchor. Hundreds of GPI-anchored proteins have been identified in many eukaryotes ranging from protozoa and fungi to mammals. All protein-linked GPI anchors share a common core structure, characterized by the substructure Man (a14) GlcN (a1-6) myo-inositol-1P-lipid. Biosynthesis of GPI anchors proceeds in three stages: (i) preassembly of a GPI precursor in the ER membrane, (ii) attachment of the GPI to the C-terminus of a newly synthesized protein in the lumen of the ER, and (iii) lipid remodeling and/or carbohydrate side-chain modifications in the ER and the Golgi. Defects of GPI anchor biosynthesis gene result in a genetic disorder, paroxysmal nocturnal hemoglobinuria.


description_brief: Non-homologous end-joining
systematic_name: M7857
exact_source: hsa03450
external_details_URL: http://www.genome.jp/pathway/hsa03450
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Nonhomologous end joining (NHEJ) eliminates DNA double-strand breaks (DSBs) by direct ligation. NHEJ involves binding of the KU heterodimer to double-stranded DNA ends, recruitment of DNA-PKcs (MRX complex in yeast), processing of ends, and recruitment of the DNA ligase IV (LIG4)-XRCC4 complex, which brings about ligation. A recent study shows that bacteria accomplish NHEJ using just two proteins (Ku and DNA ligase), whereas eukaryotes require many factors. NHEJ repairs DSBs at all stages of the cell cycle, bringing about the ligation of two DNA DSBs without the need for sequence homology, and so is error-prone.


description_brief: Lysosome
systematic_name: M11266
exact_source: hsa04142
external_details_URL: http://www.genome.jp/pathway/hsa04142
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Lysosomes are membrane-delimited organelles in animal cells serving as the cell's main digestive compartment to which all sorts of macromolecules are delivered for degradation. They contain more than 40 hydrolases in an acidic environment (pH of about 5). After synthesis in the ER, lysosomal enzymes are decorated with mannose-6-phosphate residues, which are recognized by mannose-6-phosphate receptors in the trans-Golgi network. They are packaged into clathrin-coated vesicles and are transported to late endosomes. Substances for digestion are acquired by the lysosomes via a series of processes including endocytosis, phagocytosis, and autophagy.


description_brief: Cardiac muscle contraction
systematic_name: M17673
exact_source: hsa04260
external_details_URL: http://www.genome.jp/pathway/hsa04260
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Contraction of the heart is a complex process initiated by the electrical excitation of cardiac myocytes (excitation-contraction coupling, ECC). In cardiac myocytes, Ca2+ influx induced by activation of voltage-dependent L-type Ca channels (DHP receptors) upon membrane depolarization triggers the release of Ca2+ via Ca2+ release channels (ryanodine receptors) of sarcoplasmic reticulum (SR) through a Ca2+ -induced Ca release (CICR) mechanism. Ca2+ ions released via the CICR mechanism diffuse through the cytosolic space to contractile proteins to bind to troponinC resulting in the release of inhibition induced by troponinI. The Ca2+ binding to troponinC thereby triggers the sliding of thin and thick filaments, that is, the activation of a crossbridge and subsequent cardiac force development and/or cell shortening. Recovery occurs as Ca2+ is pumped out of the cell by the Na+/Ca2+ exchanger (NCX) or is returned to the sarcoplasmic reticulum (SR) by sarco(endo)plasmic Ca2+ -ATPase (SERCA) pumps on the non-junctional region of the SR.


description_brief: Taste transduction
systematic_name: M5785
exact_source: hsa04742
external_details_URL: http://www.genome.jp/pathway/hsa04742
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  All taste pathways are proposed to converge on common elements that mediate a rise in intracellular Ca2+ followed by neurotransmitter release. Na+ salt depolarizes taste cells by passive influx of Na+ through the amiloride-sensitive Na+ channel (ENaC). Acids depolarize taste cells by a variety of mechanisms, including influx of protons (H+) through ENaC and a proton-gated cation channel (MDEG). Two putative umami receptors have been identified: a truncated variant of the metabotropic glutamate receptor mGluR4 and the heterodimer, T1R1 + T1R3. Umami receptors are coupled to a signaling pathway involving activation of PLCbeta2, production of IP3 and diacylglycerol, release of Ca2+ from intracellular stores and activation of a transient receptor potential channel, TRPM5. Bitter compounds, such as denatonium and PROP, activate particular T2R/TRB isoforms, which activate gustducin heterotrimers. Activated alpha-gustducin stimulates PDE to hydrolyze cAMP, whereas betagamma subunits activate PLCbeta2 to generate IP3, which leads to release of Ca2+ from internal stores. Artificial sweeteners activate GPCRs (T1R heterodimers) apparently linked via PLC to IP3 production and release of Ca2+ from intracellular stores. Sugars apparently activate GPCRs linked via AC to cAMP production which, in turn, may inhibit basolateral K+ channels through phosphorylation by cAMP-activated protein kinase A (PKA).


description_brief: Proximal tubule bicarbonate reclamation
systematic_name: M4361
exact_source: hsa04964
external_details_URL: http://www.genome.jp/pathway/hsa04964
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  One of the major tasks of the renal proximal tubule (PT) is to secrete acid into the tubule lumen, thereby reabsorbing approximately 80% of the filtered bicarbonate (HCO3(-)), as well as generating new HCO3(-) for regulating blood pH. In the tubular lumen, filtered HCO3(-) combines with H(+) in a reaction catalyzed by CA IV. The CO2 thus produced rapidly diffuses into the tubular cells and is combined with water to produce intracellular H(+) and HCO3(-), catalyzed by soluble cytoplasmic CA II. HCO3(-) is then cotransported with Na(+) into blood via the NBC-1. The intracellular H(+) produced by CA II is secreted into the tubular lumen predominantly via the NHE-3. The PT creates the new HCO3(-) by taking glutamine and metabolizing it to two molecules each of NH4(+) and HCO3(-). The NH4(+) is excreted into the tubular lumen, and the HCO3(-) , which is new HCO3(-) , is returned to the blood, where it replaces the HCO3(-) lost earlier in the titration of nonvolatile acids.


description_brief: Pathogenic Escherichia coli infection
systematic_name: M2333
exact_source: hsa05130
external_details_URL: http://www.genome.jp/pathway/hsa05130
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Eenteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) are closely related pathogenic strains of Escherichia coli. The hallmark of EPEC/EHEC infections is induction of attaching and effacing (A/E) lesions that damage intestinal epithelial cells. The capacity to form A/E lesions is encoded mainly by the locus of enterocyte effacement (LEE) pathogenicity island. Tir, Map, EspF, EspG are known LEE-encoded effector proteins secreted via the type III secretion system, which is also LEE-encoded, into the host cell. EPEC and EHEC Tir's link the extracellular bacterium to the cell cytoskeleton. Map and EspF are involved in mitochondrion membrane permeabilization. EspG interacts with tubulins and stimulates microtubule destabilization. LEE-encoded adhesin or intimin (Eae) is exported via the general secretory pathway to the periplasm, where it is inserted into the outer membrane. In addition to Tir, two potential host cell-carried intimin receptors, beta1 integrin (ITGB1) and nucleolin (NCL), have so far been identified. The distinguishing feature of EHEC is the elaboration of Shiga-like toxin (Stx). Stx cleaves ribosomal RNA, thereby disrupting protein synthesis and killing the intoxicated epithelial or endothelial cells.


description_brief: Systemic lupus erythematosus
systematic_name: M4741
exact_source: hsa05322
external_details_URL: http://www.genome.jp/pathway/hsa05322
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Systemic lupus erythematosus (SLE) is characterized by circulating IgG autoantibodies that are specific for self-antigens, such as DNA, nuclear proteins and certain cytoplasmic components. Immune complexes comprising autoantibody and self-antigen is deposited particulary in the renal glomeruli and mediate a systemic inflammatory response by activating complement or via Fc-gamma-R-mediated neutrophil and macrophage activation. Activation of complement leads to injury both through formation of the membrane attack complex (C5b-9) or by generation of the anaphylatoxin and cell activator C5a. Neutrophils and macrophages cause tissue injury by the release of oxidants and proteases.


description_brief: Primary immunodeficiency
systematic_name: M4085
exact_source: hsa05340
external_details_URL: http://www.genome.jp/pathway/hsa05340
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Primary immunodeficiencies (PIs) are a heterogeneous group of disorders, which affect cellular and humoral immunity or non-specific host defense mechanisms mediated by complement proteins, and cells such as phagocytes and natural killer (NK) cells. These disorders of the immune system cause increased susceptibility to infection, autoimmune disease, and malignancy. Most of PIs are due to genetic defects that affect cell maturation or function at different levels during hematopoiesis. Disruption of the cellular immunity is observed in patients with defects in T cells or both T and B cells. These cellular immunodeficiencies comprise 20% of all PIs. Disorders of humoral immunity affect B-cell differentiation and antibody production. They account for 70% of all PIs.


description_brief: Hypertrophic cardiomyopathy (HCM)
systematic_name: M8728
exact_source: hsa05410
external_details_URL: http://www.genome.jp/pathway/hsa05410
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological features of myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. HCM is one of the most common inherited cardiac disorders, with a prevalence in young adults of 1 in 500. Hundreds of mutations in 11 genes that encode protein constituents of the sarcomere have been identified in HCM. These mutations increase the Ca2+ sensitivity of cardiac myofilaments. Increased myofilament Ca2+ sensitivity is expected to increase the ATP utilization by actomyosin at submaximal Ca2+ concentrations, which might cause an imbalance in energy supply and demand in the heart under severe stress. The inefficient use of ATP suggests that an inability to maintain normal ATP levels could be the central abnormality. This theory might be supported by the discovery of the role of a mutant PRKAG2 gene in HCM, which in active form acts as a central sensing mechanism protecting cells from depletion of ATP supplies. The increase in the myofilament Ca2+ sensitivity well account for the diastolic dysfunction of model animals as well as human patients of HCM. It has been widely proposed that left ventricular hypertrophy is not a primary manifestation but develops as compensatory response to sarcomere dysfunction.


description_brief: Arrhythmogenic right ventricular cardiomyopathy (ARVC)
systematic_name: M16376
exact_source: hsa05412
external_details_URL: http://www.genome.jp/pathway/hsa05412
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in arrhythmia, heart failure, and sudden death. The hallmark pathological findings are progressive myocyte loss and fibrofatty replacement, with a predilection for the right ventricle. A number of genetic studies have identified mutations in various components of the cardiac desmosome that have important roles in the pathogenesis of ARVD/C. Disruption of desmosomal function by defective proteins might lead to death of myocytes under mechanical stress. The myocardial injury may be accompanied by inflammation. Since regeneration of cardiac myocytes is limited, repair by fibrofatty replacement occurs. Several studies have implicated that desmosome dysfunction results in the delocalization and nuclear translocation of plakoglobin. As a result, competition between plakoglobin and beta-catenin will lead to the inhibition of Wnt/beta-catenin signaling, resulting in a shift from a myocyte fate towards an adipocyte fate of cells. The ryanodine receptor plays a crucial part in electromechanical coupling by control of release of calcium from the sarcoplasmic reticulum into the cytosol. Therefore, defects in this receptor could result in an imbalance of calcium homeostasis that might trigger cell death.


description_brief: Dilated cardiomyopathy
systematic_name: M835
exact_source: hsa05414
external_details_URL: http://www.genome.jp/pathway/hsa05414
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Dilated cardiomyopathy (DCM) is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac death from ventricular arrhythmia. Genetically inherited forms of DCM (familial DCM) have been identified in 25-35% of patients presenting with this disease, and the inherited gene defects are an important cause of familial DCM. The pathophysiology may be separated into two categories: defects in force generation and defects in force transmission. In cases where an underlying pathology cannot be identified, the patient is diagnosed with an idiopathic DCM. Current hypotheses regarding causes of idiopathic DCM focus on chronic viral myocarditis and/or on autoimmune abnormalities. Viral myocarditis may progress to an autoimmune phase and then to progressive cardiac dilatation. Antibodies to the beta1-adrenergic receptor (beta1AR), which are detected in a substantial number of patients with idiopathic DCM, may increase the concentration of intracellular cAMP and intracellular Ca2+, a condition often leading to a transient hyper-performance of the heart followed by depressed heart function and heart failure.


systematic_name: M30412
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-153-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-153-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30413
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-8485
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-8485 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30414
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-3662
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-3662 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30415
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-607
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-607 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30416
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-616-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-616-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30417
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-371b-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-371b-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30418
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-373-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-373-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30419
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-6867-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-6867-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30420
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-12136
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-12136 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30421
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548aj-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548aj-3p, hsa-miR-548x-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30422
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-3646
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-3646 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30423
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-1277-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-1277-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30424
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-651-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-651-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30425
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-335-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-335-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30426
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-520d-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-520d-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30427
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-524-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-524-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30428
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548ae-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548ae-3p, hsa-miR-548aq-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30429
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548ah-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548ah-3p, hsa-miR-548am-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30430
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548j-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548j-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30431
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-3658
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-3658 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30432
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-570-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-570-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30433
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-5688
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-5688 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30434
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4795-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4795-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30435
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548e-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548e-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30436
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-5696
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-5696 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30437
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-340-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-340-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30438
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-let-7a-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-let-7a-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30439
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4262
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4262 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30440
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-30b-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-30b-5p, hsa-miR-30c-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30441
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-30d-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-30d-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30442
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-30e-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-30e-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30443
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-98-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-98-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30444
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-30a-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-30a-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30445
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-let-7f-1-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-let-7f-1-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30446
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-let-7b-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-let-7b-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30447
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-495-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-495-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30448
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-5582-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-5582-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30449
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4729
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4729 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30450
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4659a-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4659a-3p, hsa-miR-4659b-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30451
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-7-1-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-7-1-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30452
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-7-2-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-7-2-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30453
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-3671
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-3671 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30454
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4698
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4698 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30455
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-95-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-95-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30456
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-1468-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-1468-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30457
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548n
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548n in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30458
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4328
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4328 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30459
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548d-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548d-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30460
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548h-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548h-3p, hsa-miR-548z in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30461
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-302c-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-302c-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30462
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548bb-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548bb-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30463
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548ac
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548ac in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30464
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30465
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-23a-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-23a-3p, hsa-miR-23b-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30466
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-23c
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-23c in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30467
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-6809-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-6809-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30468
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-559
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-559 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30469
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-3121-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-3121-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30470
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-1297
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-1297 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30471
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548ar-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548ar-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30472
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-10527-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-10527-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30473
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-3529-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-3529-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30474
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4728-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4728-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30475
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-19a-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-19a-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30476
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548aw
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548aw in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30477
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-106b-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-106b-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30478
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-19b-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-19b-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30479
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548aa
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548aa, hsa-miR-548ap-3p, hsa-miR-548t-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30480
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-20a-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-20a-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30481
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-9983-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-9983-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30482
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-506-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-506-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30483
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-579-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-579-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30484
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-124-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-124-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30485
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-3680-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-3680-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30486
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-664b-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-664b-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30487
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-186-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-186-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30488
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-181a-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-181a-5p, hsa-miR-181b-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30489
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-181d-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-181d-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30490
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-181c-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-181c-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30491
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4719
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4719 in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30492
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4753-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4753-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30493
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4666a-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4666a-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30494
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-126-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-126-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30495
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548y
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548y in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30496
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-4668-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-4668-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30497
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-551b-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-551b-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30498
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548bb-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548bb-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30499
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548ar-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548ar-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30500
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-let-7c-3p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-let-7c-3p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30501
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548ad-5p
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548ad-5p, hsa-miR-548ae-5p, hsa-miR-548ay-5p, hsa-miR-548b-5p, hsa-miR-548d-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


systematic_name: M30502
external_details_URL: http://mirdb.org/cgi-bin/mature_mir.cgi?name=hsa-miR-548ak
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes predicted to be targets of miRBase v22 microRNA hsa-miR-548ak, hsa-miR-548am-5p, hsa-miR-548c-5p, hsa-miR-548h-5p, hsa-miR-548o-5p, hsa-miR-548au-5p in miRDB v6.0 with MirTarget v4 prediction scores > 80 (high confidence targets).


