Retracted Article: MiR-148a agomir based targeting of c-Met and Her-3 is able to attenuate EGFR-T790M mutation driven gefitinib and erlotinib resistance in non-small cell lung cancer cells

Abstract

MiR-148a inhibits NSCLC progression. Whether miR-148a would reduce EGFR tyrosine kinase inhibitor (TKI) resistance of NSCLC cells remains underexplored. In this study, 5 NSCLC patients received surgery and gefitinib treatment but developed pleural metastasis. Patients' NSCLC adopted EGFR T790M mutation. 5 naïve and 5 gefitinib-resisting NSCLC cell lines were derived from patients primary and metastatic tumor tissues, and the 5 gefitinib-resisting NSCLC cell lines were trained with erlotinib to establish the erlotinib-resisting cell lines. MiR-148a levels in cells were analyzed by qRT-PCR. miR-148a overexpression was mimicked by agomir treatment. NSCLC cell malignancy was evaluated by cell proliferation, apoptosis, colony formation and transwell invasion assays. Protein levels of c-Met, Her-3 and IGF-1R were assessed by western blotting. miRNA-mRNA interaction was investigated by luciferase reporter assay and AGO2-RIP. Transient overexpression of MET, ERBB3 or IGF1R gene was achieved by plasmid transfection. Results showed that the MiR-148a level was decreased with the development of gefitinib and erlotinib resistance and that there was an increase in malignancy in NSCLC cells in vitro. Treatment with miR-148a agomir significantly enhanced the cytotoxicity of gefitinib and erlotinib to naïve, gefitinib-resisting and erlotinib-resisting NSCLC cells in vitro while reducing their protein levels of c-Met, Her-3 and IGF-1R, the mRNAs of which were verified as direct targets of miR-148a in NSCLC cells. Restoring c-Met or Her-3 protein levels partially reduced the gefitinib and erlotinib sensitizing effect of miR-148a agomir treatment on NSCLC cells. We concluded that MiR-148a attenuated gefitinib and erlotinib resistance in non-small cell lung cancer cells with EGFR T790M mutation by targeting c-Met and Her-3 expression.