HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4

IMR OpenIR

	HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4
	Meng Yu 1; Toshinori Ozaki 2; Dan Sun 1; Haotian Xing 1; Baojun Wei 1; Jun An 1; Jieping Yang 1; Ying Gao 3; Shuangjie Liu 1; Chuize Kong 1; Yuyan Zhu 1
	2020-01-01
发表期刊	Journal of Experimental & Clinical Cancer Research
ISSN	1756-9966
卷号	39 期号:1 页码:1-13
摘要	Abstract 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.
语种	英语
文献类型	期刊论文
条目标识符	http://ir.imr.ac.cn/handle/321006/159498
专题	中国科学院金属研究所
作者单位	1.中国医科大学 2.同济大学 3.Institute of Metal Research, Chinese Academy of Sciences
推荐引用方式 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.