Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner
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Razan Sheta1,2, Zhi-Qiang Wang1,2, Magdalena Bachvarova2, Marie Plante2,3, Jean Gregoire2,3, Marie-Claude Renaud2,3, Alexandra Sebastianelli2,3, Stephane Gobeil1,4, Chantale Morin2, Elizabeth Macdonald5, Barbara Vanderhyden5 and Dimcho Bachvarov1,2
1Department of Molecular Medicine, Université Laval, Québec, Québec, Canada
2Centre de recherche du CHU de Québec, L’Hôtel-Dieu de Québec, Québec, Québec, Canada
3Department of Obstetrics and Gynecology, Université Laval, Québec, Québec, Canada
4Centre de recherche du CHU de Québec, CHUL, Québec, Québec, Canada
5Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
Dimcho Bachvarov, email: [email protected]
Keywords: Hic-5, TGFB1I1, epithelial ovarian cancer, epithelial-to-mesenchymal transition, RhoA/ROCK
Received: May 12, 2017 Accepted: June 17, 2017 Published: July 31, 2017
The molecular basis of epithelial ovarian cancer (EOC) dissemination is still poorly understood. We have previously identified the hydrogen peroxide-inducible clone-5 (Hic-5) gene as hypomethylated in high-grade (HG) serous EOC tumors, compared to normal ovarian tissues. Hic-5 is a focal adhesion scaffold protein and has been primarily studied for its role as a key mediator of TGF-β–induced epithelial-to-mesenchymal transition (EMT) in epithelial cells of both normal and malignant origin; however, its role in EOC has been never investigated.
Here we demonstrate that Hic-5 is overexpressed in advanced EOC, and that Hic-5 is upregulated upon TGFβ1 treatment in the EOC cell line with epithelial morphology (A2780s), associated with EMT induction. However, ectopic expression of Hic-5 in A2780s cells induces EMT independently of TGFβ1, accompanied with enhancement of cellular proliferation rate and migratory/invasive capacity and increased resistance to chemotherapeutic drugs. Moreover, Hic-5 knockdown in the EOC cells with mesenchymal morphology (SKOV3) was accompanied by induction of mesenchymal-to-epithelial transition (MET), followed by a reduction of their proliferative, migratory/invasive capacity, and increased drugs sensitivity in vitro, as well as enhanced tumor cell colonization and metastatic growth in vivo. The modulation of Hic-5 expression in EOC cells resulted in altered regulation of numerous EMT-related canonical pathways and was indicative for a possible role of Hic-5 in controlling EMT through a RhoA/ROCK mediated mechanism.
To our knowledge, this is the first report examining the role of Hic-5 in EOC, and its role in maintaining the mesenchymal phenotype of EOC cells independently of exogenous TGFβ1 treatment.
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