Abstract 775: MicroRNA-1205 regulation of FRYL in neuroendocrine prostate cancer

Abstract

Abstract High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (mCRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). Resistance to second generation ADTs further leads to progression to neuroendocrine PCa (NEPC), which is observed in nearly 1 in 5 men with mCRPC and is associated with low survival rates. The molecular mechanisms of progression to NEPC are, however, still unclear. Further understanding of molecular mechanisms of NEPC is critical to improving patient outcomes. The 8q24 chromosomal locus is a highly susceptible PCa region that carries high risk genetic variants associated with PCa incidence. This region also carries frequent amplifications of the PVT1 gene, a non-protein coding gene that encodes microRNA-1205 (miR-1205). We have previously reported that miR-1205 is underexpressed in PCa tissues in comparison to normal prostate tissue, and is also underexpressed in vitro in CRPC cells in comparison to non-CRPC cells. We also demonstrated that exogenous miR-1205 significantly inhibited tumor volume in CRPC tumor xenografts in mice, and that miR-1205 directly targets the putative oncogene, Fry-like (FRYL). FRYL is predicted to regulate dendritic branching leading to the hypothesis that FRYL plays a role in NEPC. To test this hypothesis, we first examined miR-1205 expression levels in PCa tissues with Gleason scores ≥8 and <8, using a cohort of histologically confirmed tissues. We observed that miR-1205 was underexpressed in tumors with Gleason scores ≥8 when compared to those with Gleason scores <8, suggesting that miR-1205 underexpression is characteristic of high grade PCa. To examine miR-1205 regulation of FRYL specifically in NEPC, we analyzed RNA sequencing data from a cohort of histologically confirmed NEPC tissues and prostate adenocarcinoma tissues obtained from TCGA via cBioPortal. We observed increased FRYL mRNA expression in NEPC tissues when compared to prostate adenocarcinoma tissues, indicating a putative oncogenic role of FRYL in NEPC. In vitro data revealed that FRYL mRNA was overexpressed and miR-1205 was significantly underexpressed after fourteen days of induced NEPC differentiation using LNCaP cells when compared to undifferentiated LNCaP cells. In conclusion, these data suggest that miR-1205 regulation of FRYL may be a critical mechanism in NEPC. Further understanding this mechanism may provide novel insights into effective therapeutic strategies for NEPC. Citation Format: Michelle K. Naidoo, Olorunseun Ogunwobi. MicroRNA-1205 regulation of FRYL in neuroendocrine prostate cancer [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 775.