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首页> 外文期刊>RSC Advances >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
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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

机译：基于MiR-148aagomir的c-Met和Her-3靶向能够减弱非小细胞肺癌细胞中EGFR-T790M突变驱动的吉非替尼和厄洛替尼耐药性

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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 na?ve 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 na?ve, 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.
机译：MiR-148a抑制NSCLC进展。 miR-148a是否会降低NSCLC细胞的EGFR酪氨酸激酶抑制剂（TKI）耐药性尚待探讨。在这项研究中，有5名NSCLC患者接受了手术和吉非替尼治疗，但发生了胸膜转移。患者的NSCLC采用了EGFR T790M突变。从患者的原发性和转移性肿瘤组织中衍生出5株纯天然和5株抗吉非替尼的NSCLC细胞系，并用厄洛替尼训练了5株抗吉非替尼的NSCLC细胞系，以建立抗厄洛替尼的细胞系。通过qRT-PCR分析细胞中的MiR-148a水平。 miR-148a过表达被agomir治疗模拟。通过细胞增殖，凋亡，集落形成和transwell侵袭试验评估了NSCLC细胞恶性程度。通过蛋白质印迹法评估c-Met，Her-3和IGF-1R的蛋白质水平。通过荧光素酶报告基因分析和AGO2-RIP研究了miRNA-mRNA的相互作用。通过质粒转染实现了MET，ERBB3或IGF1R基因的瞬时过表达。结果表明，随着吉非替尼和埃洛替尼耐药的发展，MiR-148a水平降低，并且体外NSCLC细胞的恶性程度增加。 miR-148aagomir治疗可显着增强吉非替尼和厄洛替尼对体外，耐吉非替尼和耐厄洛替尼的NSCLC细胞的细胞毒性，同时降低其c-Met，Her-3和IGF-1R，mRNA的蛋白水平证实了其中的NSR细胞是miR-148a的直接靶标。恢复c-Met或Her-3蛋白水平可部分降低miR-148a agomir治疗对NSCLC细胞的吉非替尼和厄洛替尼致敏作用。我们得出的结论是，MiR-148a通过靶向c-Met和Her-3表达来减弱具有EGFR T790M突变的非小细胞肺癌细胞中的吉非替尼和厄洛替尼耐药性。

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