Abstract A065: MicroRNA-338-5p/-421 mediated regulation of oncogenic long noncoding RNA MALAT1 abrogates prostate cancer progression and metastases

Abstract Prostate cancer (PCa) is one of the leading cause of cancer-associated death among men worldwide. Understanding the mechanism underpinning the disease pathogenesis is therefore critical in developing novel therapeutic strategies for this disease. Multiple lines of evidence suggest that noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are implicated in PCa progression and metastases. To date, great efforts have been put forth to characterize the role of miRNAs in regulating the expression of coding transcripts. However, little is known about the influence of miRNAs on the expression of noncoding transcripts such as lncRNAs. Thus, elucidating the role of miRNAs in modulating the expression of lncRNAs in PCa is crucial in order to understand their functional significance and potential utility for therapeutic interventions. Previously, we demonstrated that miR-338-5p and miR-421 exhibit tumor-suppressive properties in prostate cancer by inducing S-phase arrest, inhibiting epithelial-to-mesenchymal transition (EMT) and cancer stemness (unpublished data). Moreover, ectopic expression of these miRNAs abrogated tumor growth and distant metastases in murine xenograft model. Further, to gain insights into the biologic functions altered by miR-338-5p and miR-421, we performed global gene expression profiling of 22RV1 cells overexpressing these miRNAs. Our analysis revealed several lncRNAs deregulated by these miRNAs. One of the lncRNA found to be downregulated upon overexpression of miR-338-5p/miR-421was an oncogenic lncRNA, Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), which is known to be profoundly upregulated across many cancers including prostate. Moreover, in silico miRNA prediction tools indicated putative binding sites of miR-338-5p and miR-421 on the 3’ end of MALAT1. The binding of miR-338-5p and miR-421 on MALAT1 was further confirmed by luciferase reporter assay, indicating miRNA-mediated post-transcriptional regulation. Furthermore, analysis of RNA-seq data from The Cancer Genome Atlas for prostate adenocarcinoma (TCGA-PRAD) revealed an inverse correlation of miR-338-5p/miR-421 with MALAT1 expression in PCa patients, which in turn confirms the notion that these miRNAs suppress the expression of onco-lncRNA MALAT1. Taken together, our findings indicate that oncogenic lncRNA, MALAT1 is a target of tumor suppressor miRNAs, miR-338-5p/miR-421. More importantly, we elucidated a novel miRNA-lncRNA regulatory network that is miR-338-5p/miR-421-MALAT1 axis in PCa pathogenesis and a potential therapeutic strategy for PCa patients. Citation Format: Anjali Yadav, Vipul Bhatia, Ritika Tiwari, Shivansh Nigam, Apul Goel, Bushra Ateeq. MicroRNA-338-5p/-421 mediated regulation of oncogenic long noncoding RNA MALAT1 abrogates prostate cancer progression and metastases [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A065.