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.

Exosome-derived microRNAs contribute to prostate cancer chemoresistance

“…In the present study, miR-203 was highly expressed in exosome derived from chemoresistence PCa cells. Recently, a study found that miR-203 is upregulated in three oxaliplatin (L-OHP)-resistant metastatic colorectal cancer cell (CRC) lines and induces L-OHP resistance in CRCs by negatively regulating ataxia telangiectasia mutated kinase (20). Furthermore, miR-203 promote cisplatin resistance through suppression of the suppressor of cytokine signaling 3 (21).…”

Colorectal cancer carcinogenesis: a review of mechanisms

“…These factors are important in predicting the response to particular therapies. MicroRNAs act as positive biomarkers indicating sensitivity to therapy or as negative biomarkers signifying resistance to treatment and assisting in choosing the appropriate treatment regimen (Table 1) [164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179] .…”

MicroRNAs in Colorectal Cancer: from Diagnosis to Targeted Therapy

“…Pichler et al showed that miR-18a downregulation is associated with poor survival in patients with CRC and its expression could predict progression-free survival (PFS) in EGFR-targeted therapy (Pichler et al, 2014). Moreover, miR-203 was demonstrated to induce oxaliplatin, a common component MicroRNAs in Colorectal Cancer: from Diagnosis to Targeted Therapies combination therapeutic regimen for use in patients with metastatic CRC, and reverse chemoresistance by negatively regulating ATM kinase and Akt, respectively (Li et al, 2011;Zhou et al, 2014).…”