Abstract 4948: miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1

Abstract

Abstract Background: Castration-resistant prostate cancer (CRPC) patients are commonly treated with the chemotherapy drug, docetaxel. We previously reported that elevated miR-375 was significantly associated with poor overall survival of CRPC patients. However, the biological role and mechanism of action of miR-375 in CRPC chemotherapy remain unknown. In this study, we evaluated if miR-375 induced chemo-resistance through regulating target genes associated with multiple drug resistance. Methods: We first compared miR-375 expression level between prostate cancer tissues and normal prostate tissues using TCGA prostate cancer data. To examine the role of miR-375 in docetaxel sensitivity, we then transfected miR-375 using a pre-miRNA lentiviral vector and examined the effect of the exogenously overexpressed miR-375 on cell growth in two prostate cancer cell lines, DU145 and PC3. To determine the effect of overexpressed miR-375 on tumor growth and chemo-resistance in vivo, we subcutaneously injected cells with miR-375 overexpression into mice. Lastly, we utilized qRT-PCR and western blot assay to examine two miR-375 target genes, SEC23A and YAP1, for their expression changes after miR-375 transfection. Results: By comparing 495 tumor tissues and 52 normal tissues, we found that miR-375 was significantly overexpressed in prostate cancer tissues (8.45 fold increase, p value = 1.98E-23). Docetaxel treatment induced higher expression of miR-375 with 5.83 and 3.02 fold increases in DU145 and PC3, respectively. Interestingly, miR-375 appeared to play a contradictory role in determining prostate cancer fate. We found that miR-375 overexpression caused cell proliferation inhibition, cell cycle arrest and cell apoptosis. However, we also found that the elevated miR-375 significantly reduced cell sensitivity to docetaxel treatment in vitro, evidenced by less apoptotic cells and higher cell proliferation. Mouse models also showed that the increased miR-375 expression was resistant to docetaxel treatment, demonstrated by greater tumor weight and sizes in miR-375 transfected cells than in empty vector controls. In addition, previous studies in other laboratories have shown that SEC23A and YAP1 are miR-375 target genes and are able to reduce cancer cell growth. We therefore examined expression levels of the two genes and observed significant expression reduction of both proteins and mRNAs in the miR-375 transfected prostate cancer cell lines. TCGA dataset analysis further confirmed the negative correlations between miR-375 and the two target genes (r = -0.62 and -0.56 for SEC23A and YAP1, respectively; p<0.0001). Conclusions: miR-375 may confer chemo-resistance to docetaxel treatment during prostate cancer chemotherapy through directly targeting SEC23A and YAP1. Our study implies that miR-375 or its target genes, SEC23A or YAP1 might serve as potential diagnostic and/or therapeutic targets to overcome chemo-resistance in CRPC treatment. Citation Format: Yuan Wang, Rachel Lieberman, Jing Pan, Qi Zhang, Meijun Du, Ming You, Liang Wang. miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4948.