Abstract 1103: Tumor suppressive role of a novel microRNA at frequently deleted chromosomal locus 8p21 in prostate cancer

Abstract

Abstract Background: A frequent genomic alteration in prostate cancer (PCa) is the loss of chromosome (chr) 8p21 in approximately 30%-50% of cases. Genomic deletions of this region increase significantly with tumor grade and are associated with tumor progression and poor prognosis suggesting its role in PCa progression. A common region of loss of heterozygosity (LOH) has been mapped to the chr8p21 locus that harbors prostate-specific NKX3.1 homeobox gene. Recent genomic studies suggest that this region harbors alternative tumor suppressor genes apart from NKX3.1 that have largely remained elusive. We propose a novel, paradigm shifting hypothesis that this frequently deleted locus is associated with a cluster of microRNA genes- miR-3622a/b- that are lost in prostate cancer and play an important mechanistic role in PCa progression and metastasis. We previously demonstrated that miR-3622a plays a crucial role in PCa epithelial-to-mesenchymal transition by direct targeting of ZEB1 and SNAI2. Here we demonstrate the role of miR-3622b in prostate cancer. Methods: miRNA expression profiling was performed in microdissected prostate cancer tissues and matched adjacent normal regions by real-time PCR. To assess the functional significance of miR-3622b in PCa, we overexpressed miR-3622b/ control miRNA (miR-CON) in PCa cell lines (Du145, PC3, LNCaP) followed by functional assays.We also examined the therapeutic potential of synthetic miR-3622b mimics in vivo in a prostate cancer xenograft mouse model. Results: Expression analyses in a cohort of prostate cancer clinical specimens showed that miR-3622b expression is frequently lost in prostate cancer. Further, loss of miR-3622b expression significantly correlated with poor survival outcome and tumor progression. miR-3622b overexpression significantly decreased cellular viability and clonogenicity in PCa cell lines supporting an anti-proliferative role for this microRNA. miR-3622b overexpression also led to significant reduction of invasiveness and migration in PCa cell lines. In vivo studies demonstrated that miR-3622b overexpression induced regression of established prostate tumor xenografts. Conclusions: Collectively, these data suggest that miR-3622b plays a tumor suppressive role in PCa. We propose that frequent loss of miR-3622a/b at chr8p21 region by genetic and epigenetic mechanisms promotes prostate cancer progression and metastasis. This study supports a novel concept that connects a long standing observation of frequent loss of a chromosomal region with a novel miRNA cluster in prostate cancer. Citation Format: Nathan Bucay, Kiran Sekhon, Shahana Majid, Varahram Shahryari, Soichiro Yamamura, Z. Laura Tabatabai, Kirsten Greene, Yuichiro Tanaka, Rajvir Dahiya, Guoren Deng, Sharanjot Saini. Tumor suppressive role of a novel microRNA at frequently deleted chromosomal locus 8p21 in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1103.