Abstract 770: MiR628-5p targets Jagged 1 and inhibits growth, stemness and invasiveness of advanced prostate cancer cells

Abstract

Abstract Prostate cancer (PCa) is the most common non-cutaneous cancer in men, and according to the American Cancer Society reports, 164,690 new cases and 29,430 deaths from PCa are estimated in the United States in 2018. To reduce PCa mortality, we need a better understanding of molecular regulators of prostate carcinogenesis. MicroRNAs (MiRs) are small, non-coding RNA molecules that have been implicated in various cancers, and offer a novel opportunity to diagnose and treat cancer. We have previously identified MiR628-5p as a potential biomarker in PCa patients. This miRNA was found to be downregulated in the serum of both African American and Caucasian men with PCa compared to healthy individuals. In the present study, we further characterized the anti-cancer role of MiR628-5p in various PCa cell culture models. Results showed that MiR628-5p mimic treatment (100 nM) for 5 days significantly decreased the cell proliferation (~43% inhibition, p<0.001) in human prostate carcinoma PC3 cells compared to random mimic control. Similarly, MiR628-5p mimic treatment decreased the number of clones (clone size ≥50 cells) formed by PC3 cells by 40% (p<0.001) compared to random mimic control. Interestingly, miRNA 628-5p mimic treatment also reduced the stemness of PC3 cells as reflected in significant decrease in prostasphere size and CD44 expression. In mechanistic studies, we identified Jagged-1 as a molecular target regulated by MiR628-5p. MiR628-5p mimic treatment strongly decreased the Jagged-1 expression in several PCa cell lines (PC3, DU145, LNCaP and C4-2) as well as reduced the Jagged-1 luciferase activity. Jagged 1 inhibition by MiR628-5p was associated with reduced Notch signaling as well as decreased expression of transcription factors (snail and slug) regulating EMT. Moreover, MiR628-5p mimic treatment increased the expression of epithelial biomarkers (E-cadherin and ZO1), reduced the expression of mesenchymal marker (vimentin) and strongly inhibited the invasiveness of PC3 cells. In conclusion, we present evidence that MiR628-5p is a key regulator of prostate carcinogenesis, and offers a novel therapeutic opportunity to inhibit the growth of advanced PCa. Citation Format: Leslimar Rios-Colon, Juliet Chijioke, Anvesha Srivastava, Malathi Ramalinga, Habib Kedir, Elena Arthur, Patrice Cagle, Gagan Deep, Deepak Kumar. MiR628-5p targets Jagged 1 and inhibits growth, stemness and invasiveness of advanced prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 770.