Naidoo Michelle, Levine Fayola, Gillot Tamara, Orunmuyi Akintunde T, Olapade-Olaopa E Oluwabunmi, Ali Thahmina, Krampis Konstantinos, Pan Chun, Dorsaint Princesca, Sboner Andrea, Ogunwobi Olorunseun O
Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, United States.
Department of Biology and Biochemistry, The Graduate Center of the City University of New York, New York, NY, United States.
Front Cell Dev Biol. 2021 Jul 27;9:647485. doi: 10.3389/fcell.2021.647485. eCollection 2021.
High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (CRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). The 8q24 chromosomal locus is a region of very high PCa susceptibility that carries genetic variants associated with high risk of PCa incidence. This region also carries frequent amplifications of the PVT1 gene, a non-protein coding gene that encodes a cluster of microRNAs including, microRNA-1205 (miR-1205), which are largely understudied. Herein, we demonstrate that miR-1205 is underexpressed in PCa cells and tissues and suppresses CRPC tumors . To characterize the molecular pathway, we identified and validated fry-like (FRYL) as a direct molecular target of miR-1205 and observed its overexpression in PCa cells and tissues. FRYL is predicted to regulate dendritic branching, which led to the investigation of FRYL in neuroendocrine PCa (NEPC). Resistance toward ADT leads to the progression of treatment related NEPC often characterized by PCa neuroendocrine differentiation (NED), however, this mechanism is poorly understood. Underexpression of miR-1205 is observed when NED is induced and inhibition of miR-1205 leads to increased expression of NED markers. However, while FRYL is overexpressed during NED, FRYL knockdown did not reduce NED, therefore revealing that miR-1205 induces NED independently of FRYL.
前列腺癌（PCa）的高死亡率与转移性去势抵抗性前列腺癌（CRPC）相关，这是因为尽管进行了雄激素剥夺疗法（ADT），但雄激素受体（AR）信号仍得以维持。8q24染色体位点是PCa易感性非常高的区域，携带与PCa发病高风险相关的基因变异。该区域还经常出现PVT1基因的扩增，PVT1是一个非蛋白质编码基因，编码一组微小RNA，包括微小RNA - 1205（miR - 1205），而这些微小RNA在很大程度上尚未得到充分研究。在此，我们证明miR - 1205在PCa细胞和组织中表达下调，并能抑制CRPC肿瘤。为了阐明其分子途径，我们鉴定并验证了类fry蛋白（FRYL）是miR - 1205的直接分子靶点，并观察到其在PCa细胞和组织中过表达。预测FRYL可调节树突分支，这促使我们对神经内分泌PCa（NEPC）中的FRYL进行研究。对ADT的耐药性导致与治疗相关的NEPC进展，其通常以PCa神经内分泌分化（NED）为特征，然而，这种机制尚不清楚。当诱导NED时观察到miR - 1205表达下调，并且抑制miR - 1205会导致NED标志物表达增加。然而，虽然在NED过程中FRYL过表达，但敲低FRYL并没有降低NED，因此表明miR - 1205独立于FRYL诱导NED。
