miR-203 induces oxaliplatin resistance in colorectal cancer cells by negatively regulating ATM kinase

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• 作者：Yunfei Zhou ; Guohui Wan ; Riccardo Spizzo ; Cristina Ivan ; Rohit Mathur ; Xiaoxiao Hu ; Xiangcang Ye ; Jia Lu ; Fan Fan ; Ling Xia ; George A. Calin ; Lee M. Ellis ; Xiongbin Lu
• 关键词：Chemoresistance ; miR-203 ; ATM ; DNA damage response ; Oxaliplatin
• 刊名：Molecular Oncology
• 出版年：February, 2014
• 年：2014
• 卷：8
• 期：1
• 页码：83-92
• 全文大小：1398 K

文摘

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-na茂ve 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鈥?untranslated region (3鈥睻TR) of the ATM mRNA abolished the inhibitory effect of miR-203 on ATM. Furthermore, stable knockdown of ATM induced resistance to oxaliplatin in chemo-na茂ve CRC cells. This is the first report of oxaliplatin resistance in CRC cells induced by miR-203-mediated suppression of ATM.