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

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

Research output: Contribution to journalArticle

102 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)83-92
Number of pages10
JournalMolecular Oncology
Volume8
Issue number1
DOIs
Publication statusPublished - Feb 2014

Fingerprint

oxaliplatin
Ataxia Telangiectasia
Colorectal Neoplasms
Phosphotransferases
MicroRNAs
Ataxia Telangiectasia Mutated Proteins
Messenger RNA

Keywords

  • ATM
  • Chemoresistance
  • DNA damage response
  • MiR-203
  • Oxaliplatin

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

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

In: Molecular Oncology, Vol. 8, No. 1, 02.2014, p. 83-92.

Research output: Contribution to journalArticle

Zhou, Y, Wan, G, Spizzo, R, Ivan, C, Mathur, R, Hu, X, Ye, X, Lu, J, Fan, F, Xia, L, Calin, GA, Ellis, LM & Lu, X 2014, 'miR-203 induces oxaliplatin resistance in colorectal cancer cells by negatively regulating ATM kinase', Molecular Oncology, vol. 8, no. 1, pp. 83-92. https://doi.org/10.1016/j.molonc.2013.09.004
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. / miR-203 induces oxaliplatin resistance in colorectal cancer cells by negatively regulating ATM kinase. In: Molecular Oncology. 2014 ; Vol. 8, No. 1. pp. 83-92.
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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-na{\"i}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' 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-na{\"i}ve 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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AB - 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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