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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2017 | Research

Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel

Authors: Zhan Yang, Jin-Suo Chen, Jin-Kun Wen, Hai-Tao Gao, Bin Zheng, Chang-Bao Qu, Kai-Long Liu, Man-Li Zhang, Jun-Fei Gu, Jing-Dong Li, Yan-Ping Zhang, Wei Li, Xiao-Lu Wang, Yong Zhang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

Abstract

Background

Docetaxel-based chemotherapy failure in advanced prostate carcinoma has partly been attributed to the resistance of prostate cancer (PC) cells to docetaxel-induced apoptosis. Hence, there is an urgent need to identify mechanisms of docetaxel chemoresistance and to develop new combination therapies.

Methods

miR-193a-5p level was evaluated by qPCR in prostate tissues and cell lines, and its expression in the tissues was also examined by in situ hybridization. PC cell line (PC3 cell) was transfected with miR-193a-5p mimic or its inhibitor, and then cell apoptosis and the expression of its downstream genes Bach2 and HO-1 were detected by TUNEL staining and Western blotting. Luciferase reporter assay was used to detect the effect of miR-193a-5p and Bach2 on HO-1 expression. Xenograft animal model was used to test the effect of miR-193a-5p and docetaxel on PC3 xenograft growth.

Results

miR-193a-5p was upregulated in PC tissues and PC cell lines, with significant suppression of PC3 cell apoptosis induced by oxidative stress. Mechanistically, miR-193a-5p suppressed the expression of Bach2, a repressor of the HO-1 gene, by directly targeting the Bach2 mRNA 3′-UTR. Docetaxel treatment modestly decreased Bach2 expression and increased HO-1 level in PC3 cells, whereas a modest increase of HO-1 facilitated docetaxel-induced apoptosis. Notably, docetaxel-induced miR-193a-5p upregulation, which in turn inhibits Bach2 expression and thus relieves Bach2 repression of HO-1 expression, partly counteracted docetaxel-induced apoptosis, as evidenced by the increased Bcl-2 and decreased Bax expression. Accordingly, silencing of miR-193a-5p enhanced sensitization of PC3 cells to docetaxel-induced apoptosis. Finally, depletion of miR-193a-5p significantly reduced PC xenograft growth in vivo.

Conclusions

Silencing of miR-193a-5p or blockade of the miR-193a-5p-Bach2-HO-1 pathway may be a novel therapeutic approach for castration-resistant PC.

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Title: Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel
Authors: Zhan Yang
Jin-Suo Chen
Jin-Kun Wen
Hai-Tao Gao
Bin Zheng
Chang-Bao Qu
Kai-Long Liu
Man-Li Zhang
Jun-Fei Gu
Jing-Dong Li
Yan-Ping Zhang
Wei Li
Xiao-Lu Wang
Yong Zhang
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-017-0649-3

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Abstract

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