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

• Published in: Molecular cancer 2016-11, Vol.15 (1), p.70, Article 70
• Main Authors: Wang, Yuan, Lieberman, Rachel, Pan, Jing, Zhang, Qi, Du, Meijun, Zhang, Peng, Nevalainen, Marja, Kohli, Manish, Shenoy, Niraj K, Meng, Hui, You, Ming, Wang, Liang
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Comparative analysis; Complications and side effects; Disease Models, Animal; Docetaxel; Dosage and administration; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Female; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Humans; Male; Mice; MicroRNA; MicroRNAs - genetics; Phosphoproteins - genetics; Physiological aspects; Prognosis; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; RNA Interference; Taxoids - pharmacology; Transcription Factors; Vesicular Transport Proteins - genetics; Xenograft Model Antitumor Assays
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-016-0556-9

Treatment 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. We 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. By 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