YAP promotes erlotinib resistance in human non-small cell lung cancer cells.
YAP promotes erlotinib resistance in human non-small cell lung cancer cells.
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DOI：
10.18632/oncotarget.10458
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发表时间：
2016-08-09
期刊：
影响因子：
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通讯作者：
You L
中科院分区：
文献类型：
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作者：
Hsu PC;You B;Yang YL;Zhang WQ;Wang YC;Xu Z;Dai Y;Liu S;Yang CT;Li H;Hu B;Jablons DM;You L
是相关蛋白（雅普）是Hippo通路的主要介质，其促进癌症的发展。在这里，我们表明，雅普促进人类非小细胞肺癌（NSCLC）细胞对厄洛替尼的耐药性。我们发现通过雅普质粒转染的强制性雅普过表达促进HCC 827（外显子19缺失）细胞中的埃罗替尼抗性。在转染雅普质粒的HCC 827细胞中，GTIIC报告基因活性和Hippo下游基因AREG和CTGF的表达显著增加（P<0.05），ERBB 3 mRNA的表达也显著增加（P <0.05）。与亲本HCC 827细胞相比，HCC 827厄洛替尼耐药（ER）细胞中GTIIC报告基因活性、ERBB 3蛋白和mRNA表达均增加。小干扰RNA（siRNA）抑制雅普可增加厄洛替尼对H1975（L858 R + T790 M）细胞的细胞毒性。在雅普siRNA转染的H1975细胞中，GTIIC报告基因活性及下游基因AREG和CTGF的表达均显著降低（P<0.05）。Verteporfin，雅普抑制剂，具有与雅普siRNA相似的作用，它增加了H1975细胞对厄洛替尼的敏感性，并与厄洛替尼联合协同降低H1975细胞的迁移、侵袭和肿瘤球形成能力。我们的研究结果表明，雅普促进厄洛替尼敏感的NSCLC细胞系HCC 827中的厄洛替尼耐药性。siRNA抑制雅普增加厄洛替尼耐药NSCLC细胞系H1975对厄洛替尼的敏感性
Yes-associated protein (YAP) is a main mediator of the Hippo pathway, which promotes cancer development. Here we show that YAP promotes resistance to erlotinib in human non-small cell lung cancer (NSCLC) cells. We found that forced YAP overexpression through YAP plasmid transfection promotes erlotinib resistance in HCC827 (exon 19 deletion) cells. In YAP plasmid-transfected HCC827 cells, GTIIC reporter activity and Hippo downstream gene expression of AREG and CTGF increased significantly (P<0.05), as did ERBB3 mRNA expression (P<0.05). GTIIC reporter activity, ERBB3 protein and mRNA expression all increased in HCC827 erlotinib-resistance (ER) cells compared to parental HCC827 cells. Inhibition of YAP by small interfering RNA (siRNA) increased the cytotoxicity of erlotinib to H1975 (L858R+T790M) cells. In YAP siRNA-transfected H1975 cells, GTIIC reporter activity and downstream gene expression of AREG and CTGF decreased significantly (P<0.05). Verteporfin, YAP inhibitor had an effect similar to that of YAP siRNA; it increased sensitivity of H1975 cells to erlotinib and in combination with erlotinib, synergistically reduced migration, invasion and tumor sphere formation abilities in H1975 cells. Our results indicate that YAP promotes erlotinib resistance in the erlotinib-sensitive NSCLC cell line HCC827. Inhibition of YAP by siRNA increases sensitivity of erlotinib-resistant NSCLC cell line H1975 to erlotinib.