Authors

Irene Forno, Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Organ Transplant, University of Milan, Milan, Italy
Stefano Ferrero, Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
Maria Veronica Russo, Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Organ Transplant, University of Milan, Milan, Italy
Giacomo Gazzano, Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
Sara Giangiobbe, Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Organ Transplant, University of Milan, Milan, Italy
Emanuele Montanari, Department of Health Science, University of Milan, Milan, Italy; First Division of Urology, San Paolo Hospital, Milan, Italy
Alberto Del Nero, First Division of Urology, San Paolo Hospital, Milan, Italy
Bernardo Rocco, Division of Urology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
Giancarlo Albo, Division of Urology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
Lucia R Languino, Prostate Cancer Discover and Development Program, Wistar Institute, Philadelphia, PA, United States; Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United StatesFollow
Dario C Altieri, Prostate Cancer Discover and Development Program, Wistar Institute, Philadelphia, PA, United States; Tumor Microenvironment and Metastasis Program, Wistar Institute, Philadelphia, PA, United States
Valentina Vaira, Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy
Silvano Bosari, Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Organ Transplant, University of Milan, Milan, Italy

Document Type

Article

Publication Date

6-24-2015

Comments

This article has been peer reviewed. It was published in: PLoS ONE.

Volume 10, Issue 6, 24 June 2015, Article number e0130060.

The published version is available at DOI: 10.1371/journal.pone.0130060

Copyright © 2015 Forno et al.

Abstract

Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was associated with epigenetics silencing of the MIR34B/C locus and increased DNA copy number loss, selectively in androgen-dependent prostate cancer. In turn, loss of miR-34b resulted in downstream deregulation and overexpression of the "stemness" marker, Sox2. These findings identify loss of miR-34b as a robust biomarker for prostate cancer progression in androgen-sensitive tumors, and anticipate a potential role of progenitor/stem cell signaling in this stage of disease.

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