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

Molecular Cancer

Research

Manish Kohli¹  Niraj K. Shenoy¹  Meijun Du²  Hui Meng²  Peng Zhang²  Liang Wang²  Marja Nevalainen³  Rachel Lieberman⁴  Qi Zhang⁴  Ming You⁴  Jing Pan⁴  Yuan Wang⁵ 

[1] Department of Oncology, Mayo Clinic, 55905, Rochester, MN, USA;Department of Pathology, Medical College of Wisconsin, 53226, Milwaukee, WI, USA;Department of Pathology, Medical College of Wisconsin, 53226, Milwaukee, WI, USA;Department of Pharmacology and Toxicology, Medical College of Wisconsin, 53226, Milwaukee, WI, USA;Department of Pharmacology and Toxicology, Medical College of Wisconsin, 53226, Milwaukee, WI, USA;Key Laboratory of Hydrobiology in Liaoning Province’s Universities, Dalian Ocean University, 116021, Dalian, China;Department of Pathology, Medical College of Wisconsin, 53226, Milwaukee, WI, USA;

关键词: Prostate cancer;    miR-375;    Docetaxel resistance;    SEC23A;    YAP1;   

DOI  :  10.1186/s12943-016-0556-9

 received in 2016-06-06, accepted in 2016-11-02,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundTreatment options for metastatic castrate-resistant prostate cancer (mCRPC) are limited and typically are centered on docetaxel-based chemotherapy. We previously reported that elevated miR-375 levels were significantly associated with poor overall survival of mCRPC patients. In this study, we evaluated if miR-375 induced chemo-resistance to docetaxel through regulating target genes associated with drug resistance.MethodsWe first compared miR-375 expression level between prostate cancer tissues and normal prostate tissues using data from The Cancer Genome Atlas (TCGA). To examine the role of miR-375 in docetaxel resistance, we transfected miR-375 using a pre-miRNA lentiviral vector and examined the effects of exogenously overexpressed miR-375 on cell growth in two prostate cancer cell lines, DU145 and PC-3. To determine the effect of overexpressed miR-375 on tumor growth and chemo-resistance in vivo, we injected prostate cancer cells overexpressing miR-375 into nude mice subcutaneously and evaluated tumor growth rate during docetaxel treatment. 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.ResultsBy examining 495 tumor tissues and 52 normal tissues from TCGA data, we found that compared to normal prostate, 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 PC-3 cells, respectively. Interestingly, miR-375 appeared to play a dual role in prostate cancer proliferation. While miR-375 overexpression caused cell growth inhibition and cell apoptosis, elevated miR-375 also significantly reduced cell sensitivity to docetaxel treatment in vitro, as evidenced by decreased apoptotic cells. In vivo xenograft mouse study showed that tumors with increased miR-375 expression were more tolerant to docetaxel treatment, demonstrated by greater tumor weight and less apoptotic cells in miR-375 transfected group when compared to empty vector control group. In addition, we examined expression levels of the two miR-375 target genes (SEC23A and YAP1) and observed significant reduction in the expression at both protein and mRNA levels in 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).ConclusionsmiR-375 is involved in development of chemo-resistance to docetaxel through regulating SEC23A and YAP1 expression. Our results suggest that miR-375 or its target genes, SEC23A or YAP1, might serve as potential predictive biomarkers to docetaxel-based chemotherapy and/or therapeutic targets to overcome chemo-resistance in mCRPC stage.

【 授权许可】

CC BY   
© The Author(s). 2016