Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer
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Tetsuya Shindo1,2, Takeshi Niinuma2, Naotaka Nishiyama1, Nobuo Shinkai1, Hiroshi Kitajima2, Masahiro Kai2, Reo Maruyama3, Takashi Tokino4, Naoya Masumori1 and Hiromu Suzuki2
1Department of Urology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan
2Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
3Project for Cancer Epigenome, The Cancer Institute, Japanese Foundation for Cancer, Koto-ku, Tokyo 135-8550, Japan
4Medical Genome Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
Hiromu Suzuki, email: [email protected]
Keywords: bladder cancer; cisplatin resistance; miRNA; DNA methylation; histone modification
Abbreviations: BCa: bladder cancer; NMIBC: non-muscle invasive bladder cancer; MIBC: muscle invasive bladder cancer; CDDP: cisplatin
Received: November 07, 2017 Accepted: April 17, 2018 Published: May 11, 2018
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.
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