title: MicroRNA-616 induces androgen-independent growth of prostate cancer cells by suppressing expression of tissue factor pathway inhibitor TFPI-2.
abstract: Expression of microRNA genes is profoundly altered in cancer but their role in the development of androgen-independent prostate cancer has received limited attention as yet. In this study, we report a functional impact in prostate cancer cells for overexpression of the microRNA miR-616, which occurred consistently in cells that were androgen-independent (AI) versus androgen-dependent (AD). miR-616 overexpression was confirmed in malignant prostate tissues as opposed to benign prostate specimens. Stable miR-616 overexpression in LNCaP cells by a lentiviral-based approach stimulated AI prostate cancer cell proliferation in vitro whereas concomitantly reducing androgen-induced cell growth. More importantly, miR-616 overexpressing LNCaP cells overcame castration resistance as shown by an enhanced ability to proliferate in vivo after bilateral orchiectomy. Conversely, antagonizing miR-616 in AI prostate cancer cells yielded opposite effects. Microarray profiling and bioinformatics analysis identified the tissue factor pathway inhibitor TFPI-2 mRNA as a candidate downstream target of miR-616. In support of this candidacy, we documented interactions between miR-616 and the 3'UTR of TFPI-2 and determined TFPI-2 expression to be inversely correlated to miR-616 in a series of prostate cell lines and clinical specimens. Notably, reexpression of TFPI-2 in LNCaP cells with stable miR-616 overexpression rescued the AD phenotype, as shown by a restoration of androgen dependence and cell growth inhibition. Taken together, our findings define a functional involvement for miR-616 and TFPI-2 in the development and maintenance of androgen-independent prostate cancer.
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong. stefma@hkucc.hku.hk
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ma
authors.forename: Yuen Piu
authors.initials: YP
authors.lastname: Chan
authors.forename: Pak Shing
authors.initials: PS
authors.lastname: Kwan
authors.forename: Terence K
authors.initials: TK
authors.lastname: Lee
authors.forename: Mingxia
authors.initials: M
authors.lastname: Yan
authors.forename: Kwan Ho
authors.initials: KH
authors.lastname: Tang
authors.forename: Ming Tat
authors.initials: MT
authors.lastname: Ling
authors.forename: Juergen R
authors.initials: JR
authors.lastname: Vielkind
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.forename: Kwok Wah
authors.initials: KW
authors.lastname: Chan
mesh_terms: D000728:Androgens / Q000502:physiology; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009919:Orchiectomy; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D000728:Androgens; D006023:Glycoproteins; D035683:MicroRNAs; C021240:tissue-factor-pathway inhibitor 2