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miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells

Non-small cell lung cancer (NSCLC) is the major cause of lung cancer-related deaths. Erlotinib is an effective drug for NSCLC patients, but its effect in advanced NSCLC is compromised because of the drug resistance. The mechanism of erlotinib resistance in NSCLC is largely unknown. In the current study, we found that erlotinib treatment down-regulated miR-17-5p level in A549 cells and miR-17-5p was lower in acquired erlotinib-resistant A549 cells (A549-ER) compared with erlotinib-sensitive A549 cells. Consistently, miR-17-5p was down-regulated in the tumor tissues and the plasma of erlotinib-resistant NSCLC patients in comparison to those who are sensitive to erlotinib. Moreover, miR-17-5p mimic increased the sensitivity of A549 and A549-ER to erlotinib. In contrast, miR-17-5p inhibitor decreased the cell death of A549 and A549-ER induced by erlotinib. In addition, we also demonstrated that miR-17-5p could inhibit the mRNA and protein levels of enhancer of zeste homolog (EZH) 1, a member of the EZH family that contributes to drug resistance in several types of cancer. The luciferase assay of 3'-untranslated region (UTR) demonstrates that EZH1 is a direct target of miR-17-5p and EZH1 RNAi recapitulates the effect of miR-17-5p overexpression on erlotinib resistance. Further, mutation in seed sequence of miR-17-5p could totally abolish the sensitization of A549-ER to erlotinib induced by miR-17-5p overexpression. Our results indicate that miR-17-5p down-regulation contributes to erlotinib resistance of NSCLC by modulating its target genes such as EZH1 and plasma miR-17-5p might be a potential biomarker of erlotinib response in NSCLC patients.

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