Abstract 2083: microRNA-616 induces androgen-independent growth of prostate cancer cells through suppression of TFPI-2 expression

Abstract

Abstract Prostate cancer is the most frequently diagnosed malignant tumor and the second leading cause of cancer deaths in North America. One of the most troubling aspects of prostate cancer is that, after androgen deprivation therapy, androgen-dependent (AD) prostate cancer inescapably progresses to an androgen-independent (AI) state, for which no effective treatment has been developed. Although several molecular pathways have been suggested to explain the pathogenesis of this disease, to date the mechanisms for the development and progression of prostate cancer remain largely unknown. A better understanding of the molecular events by which AD prostate cancer cells acquire the ability to resist androgen ablation may aid in the development of more effective therapies against this disease. microRNAs (miRNAs) are a class of small, non-coding RNAs that regulate gene expression through the specific targeting of the 3’-untranslated regions (UTRs) of their target mRNAs, thereby inducing degradation of the mRNA itself or impairing its translation. The aim of this project is to examine the differential miRNA profiles in AD and AI prostate cancer. AD LNCaP-FGC and AI LNCaP-LNO, two sublines derived from the same parental prostate cancer cell line LNCaP but bearing different androgen-responsiveness, were analyzed for expression of 419 selected miRNAs. A significant overexpression of miR-616 was identified in AI LNCaP-LNO as well as in malignant prostate tissues than opposed to AD LNCaP-FGC and benign prostate tissues, respectively. Consistently, expression studies of miR-616 in cell lines and xeongrafts representing AD and AI prostate cancer stages, revealed that miR-616 is overexpressed in the more aggressive AI cells (PC3, DU145, C4-2B) when compared with the less aggressive androgen-responsive (AR) cells (22rv1), AD cells (LNCaP, LAPC-4, LAPC-9) or the immortalized, normal prostate cells (HPr-1, NPTx). Stable miR-616 overexpression and knockdown by lentiviral-based approach stimulated and diminished androgen-induced prostate cancer cell proliferation in vitro, respectively. More importantly, inhibition of miR-616 repressed prostate tumor growth in vivo and was sufficient to impart castration resistance as evident by its reduced ability to grow in an in vivo animal model where castration was performed. Subsequent integrated mRNA expression profiling findings (LNCaP-FGC with stable miR-616 overexpression or empty vector) with in silico predictions identified tumor suppressor tissue factor pathway inhibitor-2 (TFPI-2) as a candidate downstream mRNA target of miR-616. Taken together, our results suggest that miR-616 acts as an oncogene, contributing to the pathogenesis of androgen-independent prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2083.