Supplementary Table 4 from Molecular Signature of MT1-MMP: Transactivation of the Downstream Universal Gene Network in Cancer (original) (raw)
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Molecular Signature of MT1-MMP: Transactivation of the Downstream Universal Gene Network in Cancer
Cancer Research, 2008
Invasion-promoting MT1-MMP is directly linked to tumorigenesis and metastasis. Our studies led us to identify those genes, the expression of which is universally linked to MT1-MMP in multiple tumor types. Genome-wide expression profiling of MT1-MMP-overexpressing versus MT1-MMPsilenced cancer cells and a further data mining analysis of the preexisting expression database of 190 human tumors of 14 cancer types led us to identify 11 genes, the expression of which correlated firmly and universally with that of MT1-MMP (P < 0.00001). These genes included regulators of energy metabolism (NNT), trafficking and membrane fusion (SLCO2A1 and ANXA7), signaling and transcription (NR3C1, JAG1, PI3KD, and CK2A), chromatin rearrangement (SMARCA1), cell division (STK38/NDR1), apoptosis (DAPK1), and mRNA splicing (SNRPB2). Our subsequent extensive analysis of cultured cells, tumor xenografts, and cancer patient biopsies supported our data mining. Our results suggest that transcriptional reprogramming of the specific downstream genes, which themselves are associated with tumorigenesis, represents a distinctive ''molecular signature'' of the proteolytically active MT1-MMP. We suggest that the transactivation activity of MT1-MMP contributes to the promigratory cell phenotype, which is induced by this tumorigenic proteinase. The activated downstream gene network then begins functioning in unison with MT1-MMP to rework the signaling, transport, cell division, energy metabolism, and other critical cell functions and to commit the cell to migration, invasion, and, consequently, tumorigenesis.
Clinical & Experimental Metastasis, 2009
MTA (metastasis-associated gene) is a newly discovered family of cancer progression-related genes and their encoded products. MTA1, the first gene found in this family, has been repeatedly reported to be overexpressed along with its protein product MTA1 in a wide range of human cancers. In addition, the expression of MTA1/MTA1 correlates with the clinicopathological properties (malignant properties) of human cancers. MTA proteins are transcriptional co-repressors that function in histone deacetylation and are involved in the NuRD complex, which contains nucleosome remodeling and histone deacetylating molecules. MTA1 expression correlates with tumor formation in the mammary gland. In addition, MTA1 converts breast cancer cells to a more aggressive phenotype by repression of the estrogen receptor (ER) a trans-activation function through deacetylation of the chromatin in the ER-responsive element of ER-responsive genes. Furthermore, MTA1 plays an essential role in c-MYC-mediated cell transformation. Another member of this family, MTA3, is induced by estrogen and represses the expression of the transcriptional repressor Snail, a master regulator of ''epithelial to mesenchymal transitions'', resulting in the expression of the cell adhesion molecule E-cadherin and maintenance of a differentiated, normal epithelial phenotype in breast cells. In addition, tumor suppressor p53 protein is deacetylated and inactivated by both MTA1 and MTA2, leading to inhibition of growth arrest and apoptosis. Moreover, a hypoxiainducible factor-1a (HIF-1a) is also deacetylated and stabilized by MTA1, resulting in angiogenesis. Thus, MTA proteins, especially MTA1, represent a possible set of master co-regulatory molecules involved in the carcinogenesis and progression of various malignant tumors. MTA proteins are proposed to be important new tools for clinical application in cancer diagnosis and treatment.
Molecular Cancer 2014, 13:259 doi:10.1186/1476-4598-13-259
2014
This Provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. P7170, a novel inhibitor of mTORC1/mTORC2 and activin receptor-like Kinase 1
Pathway and network analysis of more than 2500 whole cancer genomes
Nature Communications, 2020
The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Gen-omes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.
Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2011
MTA1(a metastasis-associated gene) is a newly discovered human gene (residing on chromsome 14q32.3) that belongs to a family of cancer progression-related genes (MTA). The mRNA product of MTA1along with its protein product MTA1 have been reported to be over-expressed in a wide variety of animal and human tumors. For example, the expression of MTA1 and its encoded protein MTA1 correlates with the malignant properties of many human cancers, including cancers of the breast, colon, stomach, liver, prostate and others. The MTA proteins have been shown to be ubiquitinated transcriptional co-repressors that function in histone deacetylation and are part of the NuRD complex, a nucleosome remodeling and histone deacetylating complex whose stability appears to be regulated by ubiquitinated MTA1 binding to E3 ubiquitin ligase constitutive photomorphogenesis protein-1 (COP1). The MTA1 protein plays an essential role in c-MYC-mediated cell transformation, and its expression correlates with mammary gland tumor formation. In the latter, MTA1 helps convert mammary cells to more aggressive phenotypes by repression of the estrogen receptor (ER) via trans-activation through deacetylation of chromatin in the ER-responsive element of ERresponsive genes. Another member of the MTA family, MTA3, is induced by estrogen and represses the expression of the transcriptional repressor Snail, a master regulator of epithelial to mesenchymal transformation, resulting in the expression of the cell adhesion molecule E-cadherinand maintenance of a differentiated, normal epithelial phenotype in mammary cells. An important activity mediated by both MTA1 and MTA2 is deacylation and inactivation of tumor suppressor p53protein, in part by controlling its stability by inhibiting ubiquitination, leading to inhibition of growth arrest and apoptosis. Another factor deacetylated and stabilized by MTA1 NuRD complex is hypoxia-inducible factor-1α (HIF-1α), which is involved in angiogenesis. Therefore, the MTA proteins represent a possible set of master coregulatory molecules involved in the carcinogenesis and progression of various malignant tumors. As such, they could be important new tools for cancer diagnosis and treatment. MTA1 of the MTA (metastasis-associated) gene family and its encoded proteins: Toh Y, Nicolson GL molecular and regulatory functions and role in human cancer progression Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3)