Abstract 2478: miR-182-5p suppresses progression of renal cancer through cell cycle arrest by targeting lncRNA MALAT-1

Abstract

Abstract Background: Renal cell carcinoma (RCC) is a leading cause of death, accounting for nearly 14,000 (~2.4%) deaths in the United States in 2017, with clear cell carcinoma (ccRCC) being the most common histologic subtype. New and precise disease progression biomarkers are needed for early detection and follow-up. Characterization of these new biomarkers offers a new approach for the identification of novel therapeutic targets and drugs for RCC treatment. MicroRNAs (miRNAs) act as either onco-miRs or tumor suppressors in cancer. Here we show a tumor-suppressor role for miR-182-5p in ccRCC and novel regulation of cell proliferation through MALAT-1. Methods: Profiling of miR-182-5p and MALAT-1 was performed in microdissected renal cancer tissues, matched adjacent normal regions and in human renal cancer cell lines by quantitative real-time PCR. To assess the functional significance of miR-182-5p in RCC, we overexpressed miR-182-5p/control miRNA (miR-CON) in RCC cell lines (ACHN, Caki-1) followed by functional assays. We also examined the therapeutic potential of synthetic miR-182-5p mimics in vivo using a renal cancer xenograft mouse model. We performed luciferase reporter assay and Ago2-RIP assay to investigate the interaction between miR-182-5p and MALAT-1. In addition, we assessed the effects of miR-182-5p overexpression and MALAT-1 downregulation on cell cycle progression in ccRCC cell lines. Results: Expression analyses in a cohort of renal cancer clinical specimens showed that miR-182-5p expression is frequently downregulated in ccRCC. We observed that overexpression of miR-182-5p inhibited cell proliferation, colony formation, apoptosis and led to G2/M arrest, supporting an antiproliferative role for this microRNA. Overexpression of miR-182-5p led to decreased expression of CDC20 and AURKA, drivers of the cell cycle mitotic phase. Also, overexpression of miR-182-5p directly lowered the expression of MALAT-1 and knockdown of MALAT-1 mimicked the effects of miR-182-5p overexpression. Downregulation of MALAT-1 led to upregulation of p53 that ultimately downregulated CDC20, AURKA. In vivo studies demonstrated that administration of miR-182-5p caused regression of established renal tumor xenografts. Conclusions: Collectively, these data suggest that miR-182-5p plays a tumor-suppressive role in ccRCC. These findings offer new insight into role of miR-182-5p in the inhibition of ccRCC tumor growth through MALAT-1 downregulation. This study may provide rationale for development of new strategies targeting MALAT-1 through miR-182-5p for treatment of ccRCC. Citation Format: Priyanka Kulkarni, Pritha Dasgupta, Shahana Majid, Varahram Shahryari, Marisa Shiina, Yutaka Hashimoto, Nadeem Bhat, Guoren Deng, Sharanjot Saini, Soichiro Yamamura, Yuichiro Tanaka, Rajvir Dahiya. miR-182-5p suppresses progression of renal cancer through cell cycle arrest by targeting lncRNA MALAT-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2478.