Abstract PR09: MicroRNA-1205 regulation of FRYL and aggressive prostate cancer in men of African ancestry

Abstract

Abstract Men of African ancestry (moAA) have increased likelihood for development of aggressive prostate cancer (PCa). PCa deaths are often associated with castration-resistant prostate cancer (CRPC) due to maintenance of androgen receptor (AR) signaling in PCa cells following androgen ablation therapy (ADT). The 8q24 chromosomal locus is a highly susceptible PCa region that carries risk genetic variants associated with increased incidence of aggressive PCa in moAA. This region also carries frequent amplifications of the PVT1 gene, a nonprotein coding gene that encodes microRNA-1205 whose function was previously unknown. We examined miR-1205 mRNA expression in a cohort of normal (n=22), benign prostatic hyperplasia (n=42), and PCa (n=26) histologically confirmed prostatic tissues obtained from prostatectomy or transrectal biopsies of moAA in Ibadan, Nigeria. A Tukey post hoc test revealed decreased miR-1205 expression in benign prostatic hyperplasia (4.61 ± 7.5) and PCa (3.39 ± 3.53) when compared to normal tissues (6.55 ± 9.5), suggesting that miR-1205 may function as a tumor suppressor and loss of miR-1205 is characteristic of PCa in moAA. In vitro studies revealed decreased miR-1205 expression in CRPC (C4-2B and 22RV1) cells when compared to non-CRPC (LNCaP) cells, suggesting a role for miR-1205 in CRPC. Furthermore, we observed significant inhibition of tumor growth in NOD/SCID gamma mice implanted with C4-2B cells that were administered our novel synthetic analog of miR-1205 (patent pending) when compared to mice treated with a scramble oligonucleotide, indicating that miR-1205 can suppress CRPC tumors. We identified Fry-like (FRYL) as a putative target of miR-1205 using a miSVR computer algorithm and subsequently observed FRYL and AR overexpression in prostate tumors compared to normal tissue from fourteen PCa patients when whole-transcriptome analysis was performed using the Galaxy web platform. Moreover, FRYL was overexpressed in CRPC cells when compared with non-CRPC cells, further suggesting a role in CRPC development. C4-2B cells transfected with miR-1205 and the 3′ UTR of FRYL in a luciferase expressing vector revealed a significant decrease in luciferase activity when compared to control cells, indicating direct binding of miR-1205 to the 3′ UTR of FRYL. These observations strongly suggest that miR-1205 acts as a tumor suppressor by directly targeting FRYL mRNA in PCa cells. FRYL is predicted to regulate dendritic branching, leading to our hypothesis that FRYL plays a role in the development of PCa with neuroendocrine differentiation (PCND), a resulting mechanism due to ADT resistance. We observed that FRYL mRNA was overexpressed and miR-1205 was significantly underexpressed after fourteen days of inducing PCND in LNCaP cells, suggesting that miR-1205 regulation of FRYL mRNA may play a role in PCND development. Further understanding miR-1205 regulation of FRYL may provide novel insights into the molecular mechanisms of aggressive PCa. This abstract is also being presented as Poster B068. Citation Format: Michelle K. Naidoo, Fayola Levine, Tamara Gillot, Thahmina Ali, Konstantinos Krampis, Akintunde Orunmuyi, E.O. Olapade-Olaopa, Olorunseun O. Ogunwobi. MicroRNA-1205 regulation of FRYL and aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr PR09.