title: The other face of miR-17-92a cluster, exhibiting tumor suppressor effects in prostate cancer.
abstract: miR-17-92a cluster miRNAs are transcribed from a polycistronic transcription unit C13orf25 that generates six mature miRNAs, miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a that are overexpressed in lung and colon cancers. Here we show that the expression of miR-17-92a miRNAs are reduced in cancerous prostate tissues compared to uninvolved areas and also in aggressive prostate cancer cells. Restoration of expression of all members of miR-17-92a cluster showed, decreased expression of cell cycle regulatory proteins cyclin D1 and SSH1; and LIMK1 and FGD4 of RhoGTPase signaling pathway. Expression of miR-17-92a miRNAs caused decreased cell proliferation, reduced activation of AKT and MAP kinases, delayed tumorigenicity and reduced tumor growth in animals. Expression of miR-17-92a miRNAs inhibited EMT via reduced cell migration and expression of mesenchymal markers while elevating expression and surface localization of the epithelial marker E-Cadherin. Expression of miR-17-92a miRNAs improved sensitivity of androgen dependent LNCaP 104-S prostate cancer cells to anti-androgen drug Casodex, AKT inhibitor MK-2206 2HCl, and docetaxel. The androgen refractory PC-3 cells also showed increased sensitivity to docetaxel, MK-2206 2HCl and Aurora kinase inhibitor VX680 upon ectopic expression of miR-17-92a cluster miRNAs. Our data demonstrate a tumor suppressor effect of miR-17-92a cluster miRNAs in prostate cancer cells and restoration of expression of these miRNAs has a therapeutic benefit for both androgen-dependent and -independent prostate cancer cells.
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Ottman
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA.
authors.forename: Jenna
authors.initials: J
authors.lastname: Levy
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA.
authors.forename: Ratna
authors.initials: R
authors.lastname: Chakrabarti
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D005810:Multigene Family; D060787:Neoplasm Grading; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction
chemical_list: D000199:Actins; D018797:Cell Cycle Proteins; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: miR-17-92a cluster; prostate cancer; tumor suppressor