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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0556-9) contains supplementary material, which is available to authorize...

Retracted: Long noncoding RNA MALAT1 enhances the docetaxel resistance of prostate cancer cells via miR‐145‐5p‐mediated regulation of AKAP12

“…Moreover, its occurrence and recurrence rates had been significantly increasing both in developing and developed countries. [1][2][3][4] Androgen deprivation therapy (ADT) first proposed by Charles Huggins et al on their seminal observations is highly effective in controlling metastatic prostate cancer. 5 Although ADT is effective for some patients, most patients may develop castration resistance PCa (CRPC).…”

Delivery of miR-375 and doxorubicin hydrochloride by lipid-coated hollow mesoporous silica nanoparticles to overcome multiple drug resistance in hepatocellular carcinoma

“…10,13,14 Our previous study showed that miR-375 can obstruct HCC progression in mice by suppressing yes-associated protein 1 (YAP1) and astrocyte elevated gene-1 (AEG-1). 15 Moreover, AEG-1 has been shown to play a pivotal role in chemoresistance in human HCC, neuroblastoma, and breast cancer. [15][16][17][18] In cancer cells, AEG-1 promotes the expression of MDR1, resulting in increased efflux and decreased accumulation of chemotherapeutics, which leads to drug resistance.…”

“…15 Moreover, AEG-1 has been shown to play a pivotal role in chemoresistance in human HCC, neuroblastoma, and breast cancer. [15][16][17][18] In cancer cells, AEG-1 promotes the expression of MDR1, resulting in increased efflux and decreased accumulation of chemotherapeutics, which leads to drug resistance. 19,20 The molecular mechanism underlying this process includes facilitation of the association of MDR1 mRNA with polysomes by AEG-1, resulting in increased translation of MDR1 mRNA.…”

MicroRNA-375 Inhibits Growth and Enhances Radiosensitivity in Oral Squamous Cell Carcinoma by Targeting Insulin Like Growth Factor 1 Receptor

“…Recently, some researches also show that miR-375 exerts effect on the sensitivity of tumor treatments. For example, miR-375 is reported to be involved in development of chemoresistance of multiple tumor cells, such as prostate cancer, breast cancer, pancreatic cancer and gastric cancer [28-31], suggesting that miR-375 might serve as potential predictive biomarkers to chemotherapy and/or therapeutic targets to overcome chemoresistance in human cancers. Meanwhile, the correlation of miR-375 with radiosensitivity of tumor cells is also reported.…”