Abstract 3134: MicroRNA located in frequently deleted locus 8p21 regulates prostate cancer EMT, progression and metastasis

Abstract

Abstract Background The most frequent alteration in the prostate oncogenome is the loss of chromosome (chr) 8p21 that has been traditionally associated with the loss of homeodomain protein, NKX3.1, that plays important role in prostate carcinogenesis. Genomic deletions of this region increase significantly with tumor grade and are associated with poor prognosis in prostate cancer (PCa) suggesting the critical involvement of this region in PCa progression. Recent genomic studies suggest that this region harbors alternative tumor suppressor genes apart from NKX3.1. However, the identity of these tumor suppressors has largely remained elusive. Here we propose a novel, paradigm shifting hypothesis that this frequently deleted locus is associated with a microRNA (miRNA) gene- miR-3622a- that is lost in prostate cancer and play an important mechanistic role in PCa progression and metastasis by regulating Epithelial-mesenchymal transition (EMT). Methods miRNA expression profiling was performed in microdissected PCa tissues and matched adjacent normal regions by real-time PCR. To understand the functional significance of miR-3622a in PCa, we performed knockdown studies using non-transformed prostate epithelial cell line and overexpression studies employing PCa cell lines. We also examined the role of miR-3622a in vivo in an orthotopic mouse model of PCa. Further, we explored the regulatory mechanisms underlying the loss of this miRNA in prostate cancer by performing methylation analysis and copy number analysis on PCa tissues and cell lines. Results Expression analyses in a cohort of clinical specimens showed that miR-3622a expression is widely attenuated in prostate cancer and is significantly correlated with poor survival outcome and tumor progression. Functional studies showed that this miRNA inhibits PCa EMT, progression and metastasis by repression of TFs of SNAIL and ZEB family. In vivo studies demonstrated that miR-3622a overexpression reduces tumor progression significantly. Analyses of the regulatory mechanisms underlying low miR-3622a expression in clinical tissues and prostate cell lines suggested that apart from genomic deletions of this locus, epigenetic events such as DNA methylation regulate its expression coordinately. Conclusions Here we provide the first direct evidence that a miRNA gene located in a frequented deleted region of prostate cancer inhibits prostate cancer EMT, progression and metastasis. We propose that frequent loss of miR-3622a at chr8p21 region by genetic and epigenetic mechanisms leads to induction of EMT that in turn, promote PCa progression and metastasis. This study has potentially significant implications in prostate cancer field as it supports a novel concept that seeks to connect a long standing observation of frequent loss of a chromosomal region with a novel miRNA in prostate cancer. Citation Format: Shinichiro Fukuhara, Nathan Bucay, Shahana Majid, Varahram Shahryari, Laura Z. Tabatabai, Kirsten Greene, Soichiro Yamamura, Yozo Mitsui, Yuichiro Tanaka, Guoren Deng, Rajvir Dahiya, Sharanjot Saini. MicroRNA located in frequently deleted locus 8p21 regulates prostate cancer EMT, progression and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3134. doi:10.1158/1538-7445.AM2015-3134