H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer
Estrogen and hypoxia promote an aggressive phenotype in prostate cancer (PCa), driving transcription of progression-associated genes. Here, we molecularly dissect the contribution of long non-coding RNA H19 to PCa metastatic potential under combined stimuli, a topic largely uncovered. The effects of...
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doaj-26c74a13cf064801ab6edad260e7bb0e2020-11-25T01:23:19ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-08-012016401210.3390/ijms20164012ijms20164012H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate CancerLorenza Bacci0Aurora Aiello1Cristian Ripoli2Rossella Loria3Dario Pugliese4Francesco Pierconti5Dante Rotili6Lidia Strigari7Francesco Pinto8Pier Francesco Bassi9Antonello Mai10Claudio Grassi11Alfredo Pontecorvi12Rita Falcioni13Antonella Farsetti14Simona Nanni15Istituto di Patologia Medica, Università Cattolica del Sacro Cuore, 00168 Roma, ItalyIstituto di Patologia Medica, Università Cattolica del Sacro Cuore, 00168 Roma, ItalyIstituto di Fisiologia Umana, Università Cattolica del Sacro Cuore, 00168 Roma, ItalyDepartment of Research Advanced Diagnostic and Technological Innovation, Regina Elena National Cancer Institute, IRCCS, 00144 Rome, ItalyDipartimento di Urologia, Università Cattolica del Sacro Cuore, 00168 Roma, ItalyDipartimento di Anatomia, Università Cattolica del Sacro Cuore, 00168 Roma, ItalyDipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, 00185 Roma, ItalyDepartment of Medical Physics, S.Orsola Malpighi University Hospital, 40138 Bologna, ItalyFondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, ItalyFondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, ItalyDipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, 00185 Roma, ItalyIstituto di Fisiologia Umana, Università Cattolica del Sacro Cuore, 00168 Roma, ItalyIstituto di Patologia Medica, Università Cattolica del Sacro Cuore, 00168 Roma, ItalyDepartment of Research Advanced Diagnostic and Technological Innovation, Regina Elena National Cancer Institute, IRCCS, 00144 Rome, ItalyInstitute of Cell Biology and Neurobiology, National Research Council, 00168 Rome, ItalyIstituto di Patologia Medica, Università Cattolica del Sacro Cuore, 00168 Roma, ItalyEstrogen and hypoxia promote an aggressive phenotype in prostate cancer (PCa), driving transcription of progression-associated genes. Here, we molecularly dissect the contribution of long non-coding RNA H19 to PCa metastatic potential under combined stimuli, a topic largely uncovered. The effects of estrogen and hypoxia on H19 and cell adhesion molecules’ expression were investigated in PCa cells and PCa-derived organotypic slice cultures (OSCs) by qPCR and Western blot. The molecular mechanism was addressed by chromatin immunoprecipitations, overexpression, and silencing assays. PCa cells’ metastatic potential was analyzed by in vitro cell-cell adhesion, motility test, and trans-well invasion assay. We found that combined treatment caused a significant H19 down-regulation as compared with hypoxia. In turn, H19 acts as a transcriptional repressor of cell adhesion molecules, as revealed by up-regulation of both β3 and β4 integrins and E-cadherin upon H19 silencing or combined treatment. Importantly, H19 down-regulation and β integrins induction were also observed in treated OSCs. Combined treatment increased both cell motility and invasion of PCa cells. Lastly, reduction of β integrins and invasion was achieved through epigenetic modulation of H19-dependent transcription. Our study revealed that estrogen and hypoxia transcriptionally regulate, via H19, cell adhesion molecules redirecting metastatic dissemination from EMT to a β integrin-mediated invasion.https://www.mdpi.com/1422-0067/20/16/4012lncRNAestrogenhypoxiaprostate cancertumor metastasisH19epigenetic modulatorsbiomolecular analysistargeted therapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lorenza Bacci Aurora Aiello Cristian Ripoli Rossella Loria Dario Pugliese Francesco Pierconti Dante Rotili Lidia Strigari Francesco Pinto Pier Francesco Bassi Antonello Mai Claudio Grassi Alfredo Pontecorvi Rita Falcioni Antonella Farsetti Simona Nanni |
spellingShingle |
Lorenza Bacci Aurora Aiello Cristian Ripoli Rossella Loria Dario Pugliese Francesco Pierconti Dante Rotili Lidia Strigari Francesco Pinto Pier Francesco Bassi Antonello Mai Claudio Grassi Alfredo Pontecorvi Rita Falcioni Antonella Farsetti Simona Nanni H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer International Journal of Molecular Sciences lncRNA estrogen hypoxia prostate cancer tumor metastasis H19 epigenetic modulators biomolecular analysis targeted therapy |
author_facet |
Lorenza Bacci Aurora Aiello Cristian Ripoli Rossella Loria Dario Pugliese Francesco Pierconti Dante Rotili Lidia Strigari Francesco Pinto Pier Francesco Bassi Antonello Mai Claudio Grassi Alfredo Pontecorvi Rita Falcioni Antonella Farsetti Simona Nanni |
author_sort |
Lorenza Bacci |
title |
H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer |
title_short |
H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer |
title_full |
H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer |
title_fullStr |
H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer |
title_full_unstemmed |
H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer |
title_sort |
h19-dependent transcriptional regulation of β3 and β4 integrins upon estrogen and hypoxia favors metastatic potential in prostate cancer |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-08-01 |
description |
Estrogen and hypoxia promote an aggressive phenotype in prostate cancer (PCa), driving transcription of progression-associated genes. Here, we molecularly dissect the contribution of long non-coding RNA H19 to PCa metastatic potential under combined stimuli, a topic largely uncovered. The effects of estrogen and hypoxia on H19 and cell adhesion molecules’ expression were investigated in PCa cells and PCa-derived organotypic slice cultures (OSCs) by qPCR and Western blot. The molecular mechanism was addressed by chromatin immunoprecipitations, overexpression, and silencing assays. PCa cells’ metastatic potential was analyzed by in vitro cell-cell adhesion, motility test, and trans-well invasion assay. We found that combined treatment caused a significant H19 down-regulation as compared with hypoxia. In turn, H19 acts as a transcriptional repressor of cell adhesion molecules, as revealed by up-regulation of both β3 and β4 integrins and E-cadherin upon H19 silencing or combined treatment. Importantly, H19 down-regulation and β integrins induction were also observed in treated OSCs. Combined treatment increased both cell motility and invasion of PCa cells. Lastly, reduction of β integrins and invasion was achieved through epigenetic modulation of H19-dependent transcription. Our study revealed that estrogen and hypoxia transcriptionally regulate, via H19, cell adhesion molecules redirecting metastatic dissemination from EMT to a β integrin-mediated invasion. |
topic |
lncRNA estrogen hypoxia prostate cancer tumor metastasis H19 epigenetic modulators biomolecular analysis targeted therapy |
url |
https://www.mdpi.com/1422-0067/20/16/4012 |
work_keys_str_mv |
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