title: miR-34 cooperates with p53 in suppression of prostate cancer by joint regulation of stem cell compartment.
abstract: The miR-34 family was originally found to be a direct target of p53 and is a group of putative tumor suppressors. Surprisingly, mice lacking all mir-34 genes show no increase in cancer formation by 18 months of age, hence placing the physiological relevance of previous studies in doubt. Here, we report that mice with prostate epithelium-specific inactivation of mir-34 and p53 show expansion of the prostate stem cell compartment and develop early invasive adenocarcinomas and high-grade prostatic intraepithelial neoplasia, whereas no such lesions are observed after inactivation of either the mir-34 or p53 genes alone by 15 months of age. Consistently, combined deficiency of p53 and miR-34 leads to acceleration of MET-dependent growth, self-renewal, and motility of prostate stem/progenitor cells. Our study provides direct genetic evidence that mir-34 genes are bona fide tumor suppressors and identifies joint control of MET expression by p53 and miR-34 as a key component of prostate stem cell compartment regulation, aberrations in which may lead to cancer.
authors.affiliation: Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Chieh-Yang
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Chang-Il
authors.initials: CI
authors.lastname: Hwang
authors.affiliation: Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY 14853, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Corney
authors.affiliation: Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Flesken-Nikitin
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität, 80337 Munich, Germany.
authors.forename: Longchang
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität, 80337 Munich, Germany.
authors.forename: Gülfem Meryem
authors.initials: GM
authors.lastname: Öner
authors.affiliation: Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Munroe
authors.affiliation: Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY 14853, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Schimenti
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität, 80337 Munich, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
authors.affiliation: Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY 14853, USA. Electronic address: an58@cornell.edu.
authors.forename: Alexander Yu
authors.initials: AY
authors.lastname: Nikitin
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D019859:Proto-Oncogene Proteins c-met