title: Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression.
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.
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Organ Transplant, University of Milan, Milan, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Forno
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrero
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Organ Transplant, University of Milan, Milan, Italy.
authors.forename: Maria Veronica
authors.initials: MV
authors.lastname: Russo
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Gazzano
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Organ Transplant, University of Milan, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Giangiobbe
authors.affiliation: Department of Health Science, University of Milan, Milan, Italy; First Division of Urology, San Paolo Hospital, Milan, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Montanari
authors.affiliation: First Division of Urology, San Paolo Hospital, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Del Nero
authors.affiliation: Division of Urology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Rocco
authors.affiliation: Division of Urology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Albo
authors.affiliation: Prostate Cancer Discover and Development Program, The Wistar Institute, Philadelphia, PA, United States of America; Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States of America.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
authors.affiliation: Prostate Cancer Discover and Development Program, The Wistar Institute, Philadelphia, PA, United States of America; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, United States of America.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaira
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Organ Transplant, University of Milan, Milan, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology
chemical_list: D014408:Biomarkers, Tumor; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors