Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel
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 com...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-12-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-017-0649-3 |
| _version_ | 1828792548136583168 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zhan Yang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T03:10:23Z |
| format | Article |
| id | doaj.art-fbf294aeb114404cb53a07521614f8ed |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-12T03:10:23Z |
| publishDate | 2017-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-fbf294aeb114404cb53a07521614f8ed2022-12-22T00:40:25ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662017-12-0136111510.1186/s13046-017-0649-3Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxelZhan Yang0Jin-Suo Chen1Jin-Kun Wen2Hai-Tao Gao3Bin Zheng4Chang-Bao Qu5Kai-Long Liu6Man-Li Zhang7Jun-Fei Gu8Jing-Dong Li9Yan-Ping Zhang10Wei Li11Xiao-Lu Wang12Yong Zhang13Department of Urology, The Second Hospital of Hebei Medical UniversityDepartment of Urology, The Second Hospital of Hebei Medical UniversityDepartment of Biochemistry and Molecular Biology, Ministry of Education of China, Hebei Medical UniversityDepartment of Urology, The Second Hospital of Hebei Medical UniversityDepartment of Biochemistry and Molecular Biology, Ministry of Education of China, Hebei Medical UniversityDepartment of Urology, The Second Hospital of Hebei Medical UniversityDepartment of Urology, The Second Hospital of Hebei Medical UniversityDepartment of Biochemistry and Molecular Biology, Ministry of Education of China, Hebei Medical UniversityDepartment of Urology, The Second Hospital of Hebei Medical UniversityDepartment of Urology, The Second Hospital of Hebei Medical UniversityDepartment of Urology, The Second Hospital of Hebei Medical UniversityDepartment of Urology, The Second Hospital of Hebei Medical UniversityDepartment of Urology, The Second Hospital of Hebei Medical UniversityDepartment of Urology, The Second Hospital of Hebei Medical UniversityAbstract 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.http://link.springer.com/article/10.1186/s13046-017-0649-3miR-193a-5pProstate cancerDocetaxelChemoresistanceHO-1Bach2 |
| spellingShingle | 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 Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel Journal of Experimental & Clinical Cancer Research miR-193a-5p Prostate cancer Docetaxel Chemoresistance HO-1 Bach2 |
| title | Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel |
| title_full | Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel |
| title_fullStr | Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel |
| title_full_unstemmed | Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel |
| title_short | Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel |
| title_sort | silencing of mir 193a 5p increases the chemosensitivity of prostate cancer cells to docetaxel |
| topic | miR-193a-5p Prostate cancer Docetaxel Chemoresistance HO-1 Bach2 |
| url | http://link.springer.com/article/10.1186/s13046-017-0649-3 |
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