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Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner
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 sc...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669907/ https://www.ncbi.nlm.nih.gov/pubmed/29137281 http://dx.doi.org/10.18632/oncotarget.19714 |
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author | Sheta, Razan Wang, Zhi-Qiang Bachvarova, Magdalena Plante, Marie Gregoire, Jean Renaud, Marie-Claude Sebastianelli, Alexandra Gobeil, Stephane Morin, Chantale Macdonald, Elizabeth Vanderhyden, Barbara Bachvarov, Dimcho |
author_facet | Sheta, Razan Wang, Zhi-Qiang Bachvarova, Magdalena Plante, Marie Gregoire, Jean Renaud, Marie-Claude Sebastianelli, Alexandra Gobeil, Stephane Morin, Chantale Macdonald, Elizabeth Vanderhyden, Barbara Bachvarov, Dimcho |
author_sort | Sheta, Razan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5669907 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56699072017-11-09 Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner Sheta, Razan Wang, Zhi-Qiang Bachvarova, Magdalena Plante, Marie Gregoire, Jean Renaud, Marie-Claude Sebastianelli, Alexandra Gobeil, Stephane Morin, Chantale Macdonald, Elizabeth Vanderhyden, Barbara Bachvarov, Dimcho Oncotarget Research Paper 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. Impact Journals LLC 2017-07-31 /pmc/articles/PMC5669907/ /pubmed/29137281 http://dx.doi.org/10.18632/oncotarget.19714 Text en Copyright: © 2017 Sheta et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Sheta, Razan Wang, Zhi-Qiang Bachvarova, Magdalena Plante, Marie Gregoire, Jean Renaud, Marie-Claude Sebastianelli, Alexandra Gobeil, Stephane Morin, Chantale Macdonald, Elizabeth Vanderhyden, Barbara Bachvarov, Dimcho Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner |
title | Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner |
title_full | Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner |
title_fullStr | Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner |
title_full_unstemmed | Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner |
title_short | Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner |
title_sort | hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a tgfβ1-independent manner |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669907/ https://www.ncbi.nlm.nih.gov/pubmed/29137281 http://dx.doi.org/10.18632/oncotarget.19714 |
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