miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1.
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 and YAP1, respectively; p < 0.0001).



miR-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.
Key Laboratory of Hydrobiology in Liaoning Province's Universities, Dalian Ocean University, Dalian, 116021, China.|Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Yuan
Y
Wang
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Rachel
R
Lieberman
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Jing
J
Pan
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Qi
Q
Zhang
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Meijun
M
Du
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Peng
P
Zhang
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.|Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Marja
M
Nevalainen
Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
Manish
M
Kohli
Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
Niraj K
NK
Shenoy
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Hui
H
Meng
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Ming
M
You
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. liwang@mcw.edu.
Liang
L
Wang
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D034622:RNA Interference; D043823:Taxoids / Q000494:pharmacology; D014157:Transcription Factors; D033921:Vesicular Transport Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; C512739:SEC23A protein, human; D043823:Taxoids; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000077143:Docetaxel
Docetaxel resistance; Prostate cancer; SEC23A; YAP1; miR-375