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HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4
Meng Yu1; Toshinori Ozaki2; Dan Sun1; Haotian Xing1; Baojun Wei1; Jun An1; Jieping Yang1; Ying Gao3; Shuangjie Liu1; Chuize Kong1; Yuyan Zhu1
2020-01-01
Source PublicationJournal of Experimental & Clinical Cancer Research
ISSN1756-9966
Volume39Issue:1Pages:1-13
AbstractAbstract Background Chemo-resistance of bladder cancer has been considered to be one of the serious issues to be solved. In this study, we revealed pivotal role of miR-424 in the regulation of CDDP sensitivity of bladder cancer cells. Methods The cytotoxicity of cisplatin and effect of miR-424 were assessed by flow cytometry and TUNEL. Transcriptional regulation of miR-424 by HIF-1α was assessed by Chromatin immunoprecipitation (ChIP). Effect of miR-424 on expression of UNC5B, SIRT4 (Sirtuin4) and apoptotic markers was measured by QRT-PCR and/or Western blot. The regulation of miR-424 for UNC5B and SIRT4 were tested by luciferase reporter assay. The 5637-inoculated nude mice xenograft model was used for the in vivo study. The clinical significance of miR-424 was demonstrated mainly through data mining and statistical analysis of TCGA. Results In this study, we have found for the first time that cisplatin (CDDP) induces the expression of miR-424 in a HIF-1α-dependent manner under normoxia, and miR-424 plays a vital role in the regulation of CDDP resistance of bladder cancer cells in vitro. Mechanistically, we have found that UNC5B and SIRT4 are the direct downstream target genes of miR-424. CDDP-mediated suppression of xenograft bladder tumor growth was prohibited by the addition of miR-424, whereas ectopic expression of UNC5B or SIRT4 partially restored miR-424-dependent decrease in CDDP sensitivity of bladder cancer 5637 and T24 cells. Moreover, knockdown of UNC5B or SIRT4 prohibited CDDP-mediated proteolytic cleavage of PARP and also decreased CDDP sensitivity of these cells. Consistently, the higher expression levels of miR-424 were closely associated with the poor clinical outcome of the bladder cancer patients. There existed a clear inverse relationship between the expression levels of miR-424 and pro-apoptotic UNC5B or SIRT4 in bladder cancer tissues. Conclusions Collectively, our current results strongly suggest that miR-424 tightly participates in the acquisition/maintenance of CDDP-resistant phenotype of bladder cancer cells through down-regulation of its targets UNC5B and SIRT4, and thus combination chemotherapy of CDDP plus HIF-1α/miR-424 inhibition might have a significant impact on hypoxic as well as normoxic bladder cancer cells.
Language英语
Document Type期刊论文
Identifierhttp://ir.imr.ac.cn/handle/321006/159498
Collection中国科学院金属研究所
Affiliation1.中国医科大学
2.同济大学
3.Institute of Metal Research, Chinese Academy of Sciences
Recommended Citation
GB/T 7714
Meng Yu,Toshinori Ozaki,Dan Sun,et al. HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4[J]. Journal of Experimental & Clinical Cancer Research,2020,39(1):1-13.
APA Meng Yu.,Toshinori Ozaki.,Dan Sun.,Haotian Xing.,Baojun Wei.,...&Yuyan Zhu.(2020).HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4.Journal of Experimental & Clinical Cancer Research,39(1),1-13.
MLA Meng Yu,et al."HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4".Journal of Experimental & Clinical Cancer Research 39.1(2020):1-13.
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