中文摘要：

背景与目的：肝细胞生长因子（hepatocyte growth factor,HGF）诱导敏感非小细胞肺癌（nonsmall cell lung cancer,NSCLC）细胞对表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI）耐药,其机制与c-Met激活有关。本研究探讨c-Met抑制剂SU11274逆转HGF诱导的不同EGFR基因型NSCLC细胞株对吉非替尼耐药及逆转耐药机制。方法：选择人NSCLC细胞株PC9（EGFR突变型）、H292（EGFR野生型）和A549（EGFR野生型）,应用吉非替尼和SU11274单独或联合作用于HGF诱导的细胞株。实验分为6组：C组（不加药对照组）、H组（HGF处理组）、G组（吉非替尼处理组）、S组（SU11274处理组）、HG组（HGF＋吉非替尼处理组）和HGS组（HGF＋吉非替尼＋SU11274处理组）。MTT法检测对细胞增殖的影响,流式细胞术检测细胞凋亡的影响;应用蛋白质印迹法（Western blot）检测细胞中c-Met及其下游通道Stat3、Akt和Erk1/2蛋白表达水平。结果：吉非替尼对3种细胞的生长抑制作用均呈浓度依赖性,HGF处理能够缓解吉非替尼的增殖抑制作用（P〈0.05）;不同浓度吉非替尼联合SU11274作用于HGF诱导细胞时,3种细胞株存活率比吉非替尼单独作用于HGF诱导细胞时明显降低（P〈0.05）;HGS组的细胞凋亡比HG组明显增加（P〈0.05）;HGS组的c-Met、Stat3、Akt和Erk1/2活化蛋白量比HG组明显减少。结论：c-Met抑制剂SU11274可逆转HGF诱导的不同EGFR基因型NSCLC细胞株对吉非替尼耐药,其机制可能与抑制HGF活化的c-Met及其下游通道蛋白表达有关。

英文摘要：

Background and purpose：Hepatocyte growth factor （HGF） induce epidermal growth factor receptor-tyrosine kinase inhibitor （EGFR-TKI） resistance in non-small cell lung cancer （NSCLC） cells, the mechanism might be related with activation of c-Met. The present study aimed to explore whether c-Met inhibitor SU11274 reverse gefitinib resistance induced by HGF in differentEGFR gene types of NSCLC.Methods：PC9 （EGFR-activating mutant）, H292 （EGFR-wild type） and A549 （EGFR-wiled） were chosen. The experiments were divided into 6 groups：C group （control）, H group （HGF）, G group （geiftinib）, S group （SU11274）, GH group （geiftinib＋HGF）, GSH group （geiftinib＋SU11274＋HGF）. The cell survival was measured by MTT assay; the cell apoptosis was measured by lfow cytometry （FCM）; the expressions of c-Met, Stat3, Akt and Erk1/2 protein were examined by Western blot.Results：Gefitinib inhibited cell growth of 3 cells lines in a dose-dependent manner, and treating with HGF could relieve inhibition of cell growth caused by geiftinib. The cell survival when treating the HGF-induced cell lines with defferent concentration of geiftinib combined with SU11274 was signiifcantly decreased than that when treating HGF-induced cell lines with geiftinib alone. In 3 cell lines, the apoptosis rate in HGS group was higher than that in HG group （P〈0.05）. In three cells lines, the p-Met, p-Stat3, p-Akt and p-Erk1/2 expressions in HGS group were lower than that in HG group （P〈0.05）.Conclusion：SU11274 reversed geiftinib resistance induced by HGF in different EGFR gene types of NSCLC cells, the mechanism might be related with inhibiting the HGF-induced activation of c-Met and its downstream signaling pathway.