胰岛素样生长因子1在非小细胞肺癌EGFR-TKIs耐药机制中的作用  

Role of insulin-like growth factor 1 in drug resistance to EGFR-TKIs in non-small cell lung cancer

作　　者：倪健[1] 徐瑛[1] 陈斌[1] 苏春霞[1] 唐亮[2] 赵印敏[2] 徐建芳[1] 

机构地区：[1]同济大学附属上海市肺科医院肿瘤科,上海200433 [2]同济大学附属上海市肺科医院中心实验室,上海200433

出　　处：《第二军医大学学报》2014年第11期1203-1208,共6页Academic Journal of Second Military Medical University

基　　金：上海市卫生局科研课题(2010045)~~

摘　　要：目的探讨胰岛素样生长因子1(IGF-1)在表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)耐药的非小细胞肺癌(NSCLC)细胞株和患者中的表达和临床意义。方法 ELISA法检测PC9、A549、H1975细胞和患者血清IGF-1水平,蛋白质印迹和免疫细胞化学法检测细胞中胰岛素样生长因子结合蛋白(IGFBP)的表达;MTT法检测吉非替尼和IGF-1受体拮抗剂BMS536924处理后的细胞增殖;收集84例接受EGFR-TKIs治疗患者的临床资料,分析IGF-1表达与临床病理特征和生存期的相关性。结果同吉非替尼敏感细胞株PC9相比,耐药细胞株H1975和A549中IGF-1表达增加(P<0.05),IGFBP表达降低;加入不同浓度的BMS536924可促进吉非替尼对耐药细胞株的增殖抑制(P<0.05)。在接受EGFR-TKIs治疗的患者中,疾病进展者的IGF-1水平较疾病控制者有所增高(P=0.052);原发性耐药者较获得性耐药者的IGF-1水平升高(P=0.02)。IGF-1表达阴性患者的生存期高于阳性患者(P=0.002)。结论 IGF-1在耐药NSCLC细胞株及患者血清中均有高表达,使用IGF-1R拮抗剂可逆转耐药细胞对EGFR-TKIs的反应;IGF-1表达与患者预后相关。Objective To investigate the expression of insulin-like growth factor 1（IGF-1）in epidermal growth factor receptor tyrosine kinase inhibitors（EGFR-TKIs）resistant non-small cell lung cancer（NSCLC）cell lines and patients,and to discuss the relevant clinical significance.Methods Levels of IGF-1were measured by ELISA kit in PC9,A549,H1975 cells and sera of EGFR-TKIs treated NSCLC patients;insulin-like growth factor-binding protein（IGFBP）expression was examined by Western blotting analysis and immunocytochemical method.Cell growth of NSCLC cells treated with gefitinib and BMS536924（antagonist of IGF-1receptor）was determined by MTT.The clinicopathological characteristics and survival period of 84 patients receiving EGFR-TKIs treatment were collected and their relationship with IGF-1expression was analyzed.Results It was found that IGF-1level in sensitive cell line PC9 was significantly higher than those in EGFR-TKIs resistant cell lines A549 and H1975（P〈0.05）,while IGFBP expression was lower than those in A549 and H1975cells.Addition of BMS536924 of different concentrations significantly promoted the inhibitory effect of gefitinib against growth of A549 and H1975cells（P〈0.05）.The patients with disease progression showed higher IGF-1expression than those without disease progression（P=0.052）,while the patients with intrinsic resistance to EGFR-TKIs had significantly higher IGF-1level than those with acquired resistance（P=0.02）.The patients with IGF-1negative expression had significantly longer survival than those with positive expression（P=0.002）.Conclusion IGF-1expression is detected in EGFR-TKIs resistant NSCLC cell lines and patients,and antagonist of IGF-1receptor can restore the sensitivity to EGFR-TKIs.The expression of IGF-1is also a prognostic factor of NSCLC patients.

关 键 词：胰岛素样生长因子1 表皮生长因子受体酪氨酸激酶抑制剂 肿瘤抗药性 非小细胞肺癌 

分 类 号：R734.2[医药卫生—肿瘤]