title: Epigenetically altered miR-193b targets cyclin D1 in prostate cancer.
abstract: Micro-RNAs (miRNA) are important regulators of gene expression and often differentially expressed in cancer and other diseases. We have previously shown that miR-193b is hypermethylated in prostate cancer (PC) and suppresses cell growth. It has been suggested that miR-193b targets cyclin D1 in several malignancies. Here, our aim was to determine if miR-193b targets cyclin D1 in prostate cancer. Our data show that miR-193b is commonly methylated in PC samples compared to benign prostate hyperplasia. We found reduced miR-193b expression (P < 0.05) in stage pT3 tumors compared to pT2 tumors in a cohort of prostatectomy specimens. In 22Rv1 PC cells with low endogenous miR-193b expression, the overexpression of miR-193b reduced CCND1 mRNA levels and cyclin D1 protein levels. In addition, the exogenous expression of miR-193b decreased the phosphorylation level of RB, a target of the cyclin D1-CDK4/6 pathway. Moreover, according to a reporter assay, miR-193b targeted the 3'UTR of CCND1 in PC cells and the CCND1 activity was rescued by expressing CCND1 lacking its 3'UTR. Immunohistochemical analysis of cyclin D1 showed that castration-resistant prostate cancers have significantly (P = 0.0237) higher expression of cyclin D1 compared to hormone-naïve cases. Furthermore, the PC cell lines 22Rv1 and VCaP, which express low levels of miR-193b and high levels of CCND1, showed significant growth retardation when treated with a CDK4/6 inhibitor. In contrast, the inhibitor had no effect on the growth of PC-3 and DU145 cells with high miR-193b and low CCND1 expression. Taken together, our data demonstrate that miR-193b targets cyclin D1 in prostate cancer.
authors.affiliation: Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Kirsi M
authors.initials: KM
authors.lastname: Kaukoniemi
authors.affiliation: Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Rauhala
authors.affiliation: Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Scaravilli
authors.affiliation: Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Latonen
authors.affiliation: Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Annala
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.affiliation: Department of Urology, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Teuvo L J
authors.initials: TL
authors.lastname: Tammela
authors.affiliation: Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
mesh_terms: D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D019938:Cyclin D1
keywords: Cyclin D1; micro-RNA; prostate cancer