Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer

Oncotarget
Tetsuya ShindoHiromu Suzuki

Abstract

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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Citations

Apr 3, 2019·Experimental and Therapeutic Medicine·Weiyun WuJuanhua Quan
Mar 7, 2020·International Journal of Molecular Sciences·Zainab Ali SyedaSu Jung Song
Jan 11, 2021·Experimental and Molecular Pathology·Mohammad TaheriMarcel E Dinger
Apr 4, 2021·International Journal of Molecular Sciences·Przemysław A StemporPaula Dobosz
Apr 4, 2021·International Journal of Molecular Sciences·Giovanni ZarrilliMatteo Fassan

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Datasets Mentioned

BETA
GSE103250

Methods Mentioned

BETA
PCR
acetylation
immunoprecipitation
ChIP-PCR
reverse transcription PCR

Software Mentioned

SDS
TargetScan
CpG

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