Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner.

Razan Sheta,Zhi-Qiang Wang,Marie-Claude Renaud,Stephane Gobeil,Elizabeth Macdonald,Alexandra Sebastianelli,Barbara Vanderhyden,Marie Plante,Chantale Morin,Magdalena Bachvarova,Dimcho Bachvarov,Jean Gregoire

doi:10.18632/oncotarget.19714

Razan Sheta, Zhi-Qiang Wang + Show 10 more

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https://doi.org/10.18632/oncotarget.19714

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Abstract

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.

Highlights

Epithelial ovarian cancer (EOC) accounts for 4% of all cancers in women and is the leading cause of death from gynecologic malignancies [1]
Using a similar approach we have recently shown that DNA hypermethylation occurs in less invasive/ early stages of ovarian tumorigenesis, while advanced disease was associated with DNA hypomethylation of a number of oncogenes, implicated in cancer progression, invasion/metastasis and probably chemoresistance [7]
Several reports indicate that hydrogen peroxide-inducible clone-5 (Hic-5) is upregulated in mesenchymal cells, but can get upregulated during the induction of the epithelial to mesenchymal transition (EMT) process, as this upregulation was shown to be essential in establishing the mesenchymal phenotype of certain epithelial cell lines [14, 19]

Summary

Introduction

Epithelial ovarian cancer (EOC) accounts for 4% of all cancers in women and is the leading cause of death from gynecologic malignancies [1]. Aberrant DNA methylation, including global hypomethylation of heterochromatin and local CpG island methylation, occurs in EOC and contributes to ovarian tumorigenesis and mechanisms of chemoresistance [3]. Using a similar approach (methylated DNA immunoprecipitation coupled to CpG island tiling arrays) we have recently shown that DNA hypermethylation occurs in less invasive/ early stages of ovarian tumorigenesis, while advanced disease was associated with DNA hypomethylation of a number of oncogenes, implicated in cancer progression, invasion/metastasis and probably chemoresistance [7]. Multiple studies have shown that TGFβ1 stimulation can induce Hic-5 expression in epithelial cells of different origins [15,16,17,18], but the exact relationship between Hic-5 function in cancer cells and its link to the TGFβ1- signal transduction pathway remains unclear. Several reports indicate that Hic-5 is upregulated in mesenchymal cells, but can get upregulated during the induction of the epithelial to mesenchymal transition (EMT) process, as this upregulation was shown to be essential in establishing the mesenchymal phenotype of certain epithelial cell lines [14, 19]

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