Abstract 274: Multifaceted function of microRNA-299-3p fosters an antitumor environment through modulation of androgen receptor and VEGFA signaling pathways in prostate cancer cells

Abstract

Abstract MicroRNAs (miRNAs) play crucial roles in the regulation of prostate cancer (PCa) through modulation of signaling pathways. Androgen receptor (AR) signaling is central to PCa and PCa therapy. The therapeutic suitability of miRNAs that target AR has not been investigated thoroughly. Here, we illustrate the clinical relevance, functional significance and therapeutic benefit of miR-299-3p, an AR targeting microRNA, in PCa progression. We noted a loss of expression of miR-299-3p in prostate tumors compared to noncancerous prostate tissue in clinical specimens. Studies on the impact of miR-299-3p restoration on AR function, phenotypic changes associated with cancer progression and involvement of the downstream components of the AR signaling pathway were conducted using in vitro and in vivo model systems. Replenishment of miR-299-3p in C4-2B, 22Rv-1, and PC-3 cells contributed to cell cycle arrest, reduced cell proliferation, migration and increased expression of apoptotic markers. Additionally, expression of miR-299-3p reduced AR, PSA and VEGFA expression. AGO-RNA pulldown experiment showed enrichment of AR, VEGFA and miR-299-3p in the RISC in the extracts of C4-2B cells overexpressing miR-299-3p. Overexpression of miR-299-3p inhibited epithelial-mesenchymal transition signaling, through inhibition of expression of Slug, TGF-Β3, phospho-AKT, and phospho-PRAS40 and up-regulation of E-cadherin. Replenishment of miR-299-3p showed reduced tumor growth in xenograft mice models. Furthermore, we also tested the benefit of miR-299-3p restoration in combination treatment with enzalutamide and docetaxel which showed a synergistic effect on drug sensitivity. In conclusion, this study has identified novel mechanisms of antitumor and antimigration functions of miR-299-3p through modulation of AR and VEGFA signaling pathways which leads to improved drug sensitivity of PCa. Citation Format: Kavya Ganapathy, Stephen Staklinski, Md Faqrul Hasan, Richard Ottman, Thomas Andl, Anders Berglund, Jong Park, Ratna Chakrabarti. Multifaceted function of microRNA-299-3p fosters an antitumor environment through modulation of androgen receptor and VEGFA signaling pathways in prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 274.