Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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The influence of WWOX tumor supressor gene on endometrial cancerogenesis

ABSTRACT: The WWOX gene is a tumor suppressor probably involved in variety of cellular processes including and is ferquently downregulated in variety of cancer types. However, its role in endometrial cancerogenesis is not well described. The aim of this study was to characterize how WWOX may be involved in endometrial cancerogenesis, how it influences the basic cancer cell features and modifies cell expression profile.Our observations suggest that in ECC1 endometrial cancer cell line increased expression of WWOX may be involved in the initiation of EMT, leading to changes in cell adhesion and motility but also indicate its suppressive role in the process of mesenchymal phenotype acquisition, resulting in reduction of aggressiveness cell features Well differentiated ECC1 endometrial cancer cells were stably transfected with WWOX cDNA.ECC1 cells transfected with an empty vector served as a control. Total mRNA was isolated to look for gene-expression differences induced by the WWOX overexpression.

ORGANISM(S): Homo sapiens

SUBMITTER: Magdalena Nowakowska

PROVIDER: E-GEOD-61041 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:WWOX expression is lost during tumor progression in many human malignancies including breast cancer. To understand the effects of loss of WWOX expression we analyzed the consequences of its silencing in normal human breast cells (MCF10F). WWOX silencing led to the formation of larger cell colonies, increased cell motility and decreased cell attachment. WWOX silenced cells demonstrated deregulated expression on genes involved in cell cycle, DNA damage response and cell motility. We detected an enrichment of targets activated by the SMAD3 transcription factor. Most notably expression of ANGPTL4, FST, PTHLH and SERPINE1 were all significantly increased upon WWOX silencing. Upregulation of these genes can be reversed by re-expressing WWOX in the previously silenced cells thus suggesting an inverse correlation between WWOX protein expression and SMAD3 transcriptional activity. Importantly, we demonstrate that WWOX physically interacts with SMAD3 protein via WW domain 1, that WWOX expression dramatically decreases SMAD3 occupancy at the ANGPTL4 and SERPINE1 promoters and significantly quenches activation of a TGFM-NM-2 responsive reporter (3TP-LUX). Furthermore, WWOX expression leads to intracellular redistribution of SMAD3 protein levels redirecting protein availability from the nuclear to the cytoplasmic compartment. Interestingly, meta-analysis of gene expression breast cancer datasets indicate that WWOX and ANGPTL4 expression, encoding a secreted protein of key relevance in breast cancer lung metastatic cells, are inversely correlated and the WWOXlo/ANGPTL4hi cluster of tumors are enriched in triple-negative and basal-like sub-types. In summary, we demonstrate that WWOX modulates SMAD3 signaling in breast cells via direct WW-domain binding and potential cytoplasmic sequestration of SMAD3 protein. Since loss of WWOX expression increases with breast cancer progression and it behaves as an inhibitor of SMAD3 transcriptional activity these observations may help explain, at least in part, the paradoxical pro-tumorigenic effects of TGFM-NM-2 signaling in advanced breast cancer. We compared two independent shRNAs: shWWOX-A and shWWOX-B with 3 biological replicates each one, targeting different regions of the WWOX transcript as a means of ruling out any potential off-target effects.

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The influence of WWOX tumor supressor gene on endometrial cancerogenesis

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