Let-7 and miR-17 promote self-renewal and drive gefitinib resistance in non-small cell lung cancer

Abstract

Epidermal growth factor receptor-tyrosinase kinase inhibitor (EGFR-TKI) resistance represents a major obstacle in the therapy of non-small cell lung cancer (NSCLC), and the underlying molecular mechanisms are unknown. In this study, it was found that let-7 family expression was downregulated and miR-17 family expression was upregulated in gefitinib-resistant PC9/GR cells compared with gefitinib-sensitive PC9 cells. The downregulation of let-7 and upregulation of miR-17 have significant clinical relevance to gefitinib resistance in NSCLC. Moreover, it was shown that downregulation of let-7 and upregulation of miR-17 promoted resistance to gefitinib by regulating the self-renewal capability of NSCLC cells. In addition, let-7 participated in the maintenance of stem cell characteristics by regulating the target gene MYC, and miR-17 participated in regulation of the cell cycle by regulating the target gene CDKN1A. In NSCLC cells, low expression of let-7 increased MYC expression to help maintain the undifferentiated status, and high expression of miR-17 decreased CDKN1A expression to help maintain the proliferative potential. Thus, both let-7 and miR-17 promoted self-renewal, which is typical of stem cell-like characteristics and resulted in gefitinib resistance. Therefore, this study demonstrated that let-7 and miR-17 were involved in the regulation of EGFR-TKI resistance, and could be used as predictive biomarkers of EGFR-TKI resistance in NSCLC.