miR-203 induces oxaliplatin resistance in colorectal cancer cells by negatively regulating ATM kinase.
miR-203 induces oxaliplatin resistance in colorectal cancer cells by negatively regulating ATM kinase.
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DOI：
10.1016/j.molonc.2013.09.004
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发表时间：
2014-02
影响因子：
6.6
通讯作者：
Lu, Xiongbin
中科院分区：
文献类型：
--
作者：
Zhou, Yunfei;Wan, Guohui;Spizzo, Riccardo;Ivan, Cristina;Mathur, Rohit;Hu, Xiaoxiao;Ye, Xiangcang;Lu, Jia;Fan, Fan;Xia, Ling;Calin, George A.;Ellis, Lee M.;Lu, Xiongbin
转移性结直肠癌（CRC）患者的化疗是标准治疗，但最终几乎所有患者都会产生耐药性。了解导致对单个化疗药物耐药的机制可能有助于确定新的靶点和药物，从而改善治疗。奥沙利铂是转移性CRC患者的常用组分联合治疗方案，但也用作有复发风险患者的辅助治疗组分。在这项研究中，无偏microRNA阵列筛选显示，miR-203 microRNA在三种奥沙利铂耐药CRC细胞系中的三种中上调，因此我们研究了miR-203在化疗耐药性中的作用。miR-203在化疗初治CRC细胞中的外源性表达诱导奥沙利铂耐药。miR-203的敲低使化疗耐药CRC细胞对奥沙利铂敏感。计算机模拟分析鉴定了共济失调毛细血管扩张突变（ATM）（DNA损伤反应的主要介质）作为miR-203的潜在靶点。ATM mRNA和蛋白水平在对奥沙利铂获得性耐药的CRC细胞中显著下调。使用TCGA数据库，我们确定了miR-203和ATM在CRC组织中的表达显著负相关。我们验证了ATM是CRC细胞中miR-203的真正靶点。在ATM mRNA的3′非翻译区（3 'UTR）突变miR-203的结合位点，可消除miR-203对ATM的抑制作用。此外，ATM的稳定敲除诱导化疗初治CRC细胞对奥沙利铂的耐药性。这是第一份关于miR-203介导的ATM抑制诱导CRC细胞奥沙利铂耐药的报告。
Chemotherapy for patients with metastatic colorectal cancer (CRC) is the standard of care, but ultimately nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may help identify novel targets and drugs that will, in turn, improve therapy. Oxaliplatin is a common component combination therapeutic regimen for use in patients with metastatic CRC, but is also used as a component of adjuvant therapy for patients at risk for recurrent disease. In this study, unbiased microRNA array screening revealed that the miR-203 microRNA is up-regulated in three of three oxaliplatin-resistant CRC cell lines, and therefore we investigated the role of miR-203 in chemoresistance. Exogenous expression of miR-203 in chemo-naïve CRC cells induced oxaliplatin resistance. Knockdown of miR-203 sensitized chemoresistant CRC cells to oxaliplatin. In silico analysis identified ataxia telangiectasia mutated (ATM), a primary mediator of the DNA damage response, as a potential target of miR-203. ATM mRNA and protein levels were significantly down-regulated in CRC cells with acquired resistance to oxaliplatin. Using TCGA database, we identified a significant reverse correlation of miR-203 and ATM expression in CRC tissues. We validated ATM as a bona fide target of miR-203 in CRC cells. Mutation of the putative miR-203 binding site in the 3′ untranslated region (3’UTR) of the ATM mRNA abolished the inhibitory effect of miR-203 on ATM. Furthermore, stable knockdown of ATM induced resistance to oxaliplatin in chemo-naïve CRC cells. This is the first report of oxaliplatin resistance in CRC cells induced by miR-203-mediated suppression of ATM.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
3.5
作者：
Gourdier, I;Del Rio, M;Pau, B
通讯作者：
Pau, B
影响因子：
3.3
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Gregory PA;Bracken CP;Smith E;Bert AG;Wright JA;Roslan S;Morris M;Wyatt L;Farshid G;Lim YY;Lindeman GJ;Shannon MF;Drew PA;Khew-Goodall Y;Goodall GJ
通讯作者：
Goodall GJ
影响因子：
45.3
作者：
Goldberg, RM;Sargent, DJ;Alberts, SR
通讯作者：
Alberts, SR
影响因子：
4.6
作者：
Jackson, Sarah J.;Zhang, Zhaojie;Yi, Rui
通讯作者：
Yi, Rui