Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer.
In this study, we identified microRNAs (miRNAs) involved in cisplatin (CDDP) resistance in bladder cancer (BCa). After establishing CDDP-resistant BCa cell lines (T24RC and EJ138RC), TaqMan arrays revealed that members of the miR-200 family (miR-200b, miR-200a and miR-429) were downregulated in T24RC as compared to parental T24 cells. miR-200b was associated with CDDP sensitivity in BCa cells, and its downregulation was associated with CpG island hypermethylation. Pharmacological demethylation using 5-aza-2'-deoxycytidine restored miR-200b expression, and the combination of 5-aza-2'-deoxycytidine + CDDP strongly inhibited T24RC cell proliferation. Microarray analysis revealed that miR-200b + CDDP induced genes involved in CDDP sensitivity or cytotoxicity, including IGFBP3, ICAM1 and TNFSF10, in the resistant cells. Expression and DNA methylation of miR-200b were inversely associated in primary BCa, and low expression/high methylation was associated with poor overall survival. These results suggest downregulation of miR-200b is associated with CDDP resistance in BCa. Epigenetic silencing of miR-200b may be a marker of CDDP resistance and a useful therapeutic target for overcoming CDDP resistance in BCa.
['Shindo|Tetsuya|T|', 'Niinuma|Takeshi|T|', 'Nishiyama|Naotaka|N|', 'Shinkai|Nobuo|N|', 'Kitajima|Hiroshi|H|', 'Kai|Masahiro|M|', 'Maruyama|Reo|R|', 'Tokino|Takashi|T|', 'Masumori|Naoya|N|', 'Suzuki|Hiromu|H|']
cisplatin resistance bladder cancer miRNA DNA methylation histone modification