Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer.
Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer.
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DOI：
10.18632/oncotarget.25326
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发表时间：
2018-05-11
期刊：
影响因子：
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通讯作者：
Suzuki H
中科院分区：
文献类型：
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作者：
Shindo T;Niinuma T;Nishiyama N;Shinkai N;Kitajima H;Kai M;Maruyama R;Tokino T;Masumori N;Suzuki H
在这项研究中，我们确定了参与膀胱癌（BCa）顺铂（CDDP）耐药的microRNAs（miRNAs）。在建立CDDP抗性BCa细胞系（T24 RC和EJ 138 RC）后，TaqMan阵列显示，与亲本T24细胞相比，miR-200家族的成员（miR-200 b、miR-200 a和miR-429）在T24 RC中下调。miR-200 b与BCa细胞对顺铂的敏感性相关，其下调与CpG岛高甲基化相关。使用5-氮杂-2 '-脱氧胞苷的药理学去甲基化恢复了miR-200 b的表达，并且5-氮杂-2'-脱氧胞苷+ CDDP的组合强烈抑制了T24 RC细胞增殖。芯片分析显示，miR-200 b + CDDP诱导的基因涉及CDDP敏感性或细胞毒性，包括IGFBP 3，ICAM 1和TNFSF 10，在耐药细胞。在原发性BCa中，miR-200 b的表达和DNA甲基化呈负相关，低表达/高甲基化与总生存率低相关。这些结果表明miR-200 b的下调与BCa中的CDDP抗性相关。miR-200 b的表观遗传沉默可能是BCa中CDDP抗性的标志物和克服CDDP抗性的有用的治疗靶点。
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.