title: miR-203 induces oxaliplatin resistance in colorectal cancer cells by negatively regulating ATM kinase.
abstract: 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.
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0173, Houston, TX 77030, USA.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0173, Houston, TX 77030, USA.
authors.forename: Guohui
authors.initials: G
authors.lastname: Wan
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Spizzo
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0173, Houston, TX 77030, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mathur
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0173, Houston, TX 77030, USA.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xiangcang
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0173, Houston, TX 77030, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: lellis@mdanderson.org.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0173, Houston, TX 77030, USA. Electronic address: xlu2@mdanderson.org.
authors.forename: Xiongbin
authors.initials: X
authors.lastname: Lu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D012007:Rectum / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; Chemoresistance; DNA damage response; Oxaliplatin; miR-203