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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：MIR-148A基于AGOMIR的C-MET和HER-3的靶向能够在非小细胞肺癌细胞中衰减EGFR-T790M突变驱动的吉非替尼和欧洛替尼抗性

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摘要

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 naive 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 naive, 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EGFR酪氨酸激酶抑制剂（TKI）NSCLC细胞的抗性仍然是缺乏缺陷的。在本研究中，5名NSCLC患者接受手术和吉替尼治疗，但发育了胸膜转移。患者的NSCLC采用EGFR T790M突变。患有患者的患者和转移性肿瘤组织的5天真和5个致吉替尼抗性NSCLC细胞系，并且用厄洛替尼培训了5种致抗灭菌的NSCLC细胞系以建立抗替替尼抗性细胞系。通过QRT-PCR分析细胞中的miR-148a水平。 MiR-148A过表达被Agomir治疗模仿。通过细胞增殖，细胞凋亡，菌落形成和Transwell侵袭测定评估NSCLC细胞恶性肿瘤。通过Western印迹评估C-Met，HER-3和IGF-1R的蛋白质水平。通过荧光素酶报告酶测定和前2-RIP研究了miRNA-mRNA相互作用。通过质粒转染实现了满足的瞬时过度表达，ERBB3或IGF1R基因。结果表明，随着吉非替尼和奥尔洛替尼的发展，MIR-148A水平降低，并且在体外，NSCLC细胞中的恶性肿瘤恶性肿瘤增加。 MiR-148a Agomir的治疗显着提高了吉替尼和厄洛替尼的细胞毒性，并在体外，在体外，在体外，在体外抵抗Naive，Gefitinib抵抗和orlotinib抵抗NSClc细胞，同时降低其蛋白质水平的C-Met，HER-3和IGF-1R，其MRNA被验证为NSCLC细胞中miR-148a的直接靶标。恢复C-Met或HER-3蛋白水平部分地降低了MIR-148A AGOMIR治疗对NMSCLC细胞的吉替尼和欧隆胆苷的敏化效果。我们得出结论，MiR-148A通过靶向C-Met和Her-3表达，在非小细胞肺癌细胞中减毒，在非小细胞肺癌细胞中的抗血红蛋白和欧隆菌属抗性。

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  • 来源
    《RSC Advances》 |2019年第37期|共8页
  • 作者

    Chen Guimin; Ye Lei; Han Yufei; Han Ping;

  • 作者单位

    Lin Yi Canc Hosp Dept Internal Med 2 Linyi Shandong Peoples R China;

    Lin Yi Canc Hosp Dept Internal Med 1 Linyi Shandong Peoples R China;

    Lin Yi Canc Hosp Dept Internal Med 2 Linyi Shandong Peoples R China;

    Linyi Peoples Hosp Dept Respirat 2 6 East Lingyuan St Linyi 276000 Shandong Peoples R China;

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  • 正文语种 eng
  • 中图分类 化学;
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