整合素β_1表达上调对非小细胞肺癌吉非替尼耐药的影响  

The role of up-regulation of integrin β_1 in resistance to gefitinib in non-small cell lung cancer

作　　者：张学兰[1] 周彩存[2] 鞠立霞[2] 

机构地区：[1]苏州大学呼吸内科,苏州215006 [2]同济大学附属上海市肺科医院肿瘤科,上海200433

出　　处：《肿瘤》2011年第6期483-488,共6页Tumor

基　　金：国家自然科学基金资助项目(编号:30873023)

摘　　要：目的:探讨整合素β1表达上调对表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptortyrosine kinase inhibitor,EGFR-TKI)吉非替尼抑制非小细胞肺癌细胞增殖以及肿瘤生长的影响。方法:将PC9、PC9/PCD(脂质体pcDNA3.1稳定转染空白对照株)和PC9/D6(脂质体稳定转染整合素β1细胞株)3株细胞经0.5μmol/L吉非替尼作用后,MTT法检测3株细胞的增殖情况。建立3株细胞的裸鼠移植瘤模型,设治疗组(3mg/kg吉非替尼)和对照组(1%Tween-80),观察肿瘤的生长情况,绘制肿瘤生长曲线,称取瘤体质量,计算抑瘤率。免疫组织化学法检测裸鼠移植瘤组织中整合素β1、EGFR和pEGFR的表达情况。结果:转染了整合素β1的PC9/D6组增殖率明显高于PC9/PCD和PC9组(P<0.05)。吉非替尼对PC9/D6裸鼠移植瘤的生长抑制最不明显,抑制率是61.38%,与PC9/PCD和PC9组比较差异具有统计学意义(P<0.01);PC9/PCD和PC9组的抑制率分别是93.54%和95.16%。PC9/D6裸鼠移植瘤中整合素β1的表达水平高于PC9/PCD和PC9组(P<0.01)。EGFR在3组之间表达的差异无统计学意义。3组裸鼠移植瘤经吉非替尼治疗后,pEGFR表达水平均有不同程度的下降,但PC9/D6治疗组中pEGFR表达水平显著高于PC9/PCD和PC9组(P<0.01)。结论:无论体内或体外实验均显示,整合素β1表达上调可降低细胞株或移植瘤对吉非替尼的敏感性,提示整合素β1可能通过一种新的耐药机制参与了肿瘤细胞对EGFR-TKI的耐药。Objective：To investigate the effects of up-regulation of integrin β1 on tumor cell proliferation and tumor growth of non-small cell lung cancer（NSCLC） inhibited by gefitinib,a epidermal growth factor receptor-tyrosine kinase inhibitor（EGFR-TKI）.Methods：Three NSCLC cell lines including PC9,PC9/PCD（transfected with empty plasmid pcDNA 3.1） and PC9/D6（transfected with integrin β1-expressed plasmid） were treated with 0.5 μmol/L gefitinib.The cell proliferation was detected by MTT assay.The graft tumors from the three cell lines in nude mice were established,respectively,and then they were randomly received 3 mg/kg gefitinib or 1% Tween-80.The tumor growth was observed and the growth curve was drawn.The tumor weight was recorded and the tumor growth inhibition rate was calculated.The expressions of integrin β1,EGFR and pEGFR in tumor tissues were examined by immunohistochemistry.Results：The proliferation rate of PC9/D6 cells transfected with integrin β1 was significantly higher than those of PC9/PCD and PC9 cells（P〈0.05）.The graft tumor growth inhibition rates were 61.38%,93.54% and 95.16% in the PC9/D6,PC9/PCD and PC9 groups,respectively;the differences between the PC9/D6 group and the PC9/PCD and PC9 groups were significant（both P〈0.01）.The expression of pEGFR was decreased in the three graft tumor groups after treating with gefitinib;however,the expression levels of pEGFR and integrin β1 in PC9/D6 group were significantly higher than those in the PC9/PCD and PC9 groups（P〈0.01）.There was no obvious difference in the expression level of EGFR among the three groups.Conclusion：The up-regulation of integrin β1 may decrease the sensitivity to gefitinib in NSCLC in vitro and in vivo.Therefore,integrin β1 may be implicated in drug resistance to EGFR-TKIs via a new mechanism.

关 键 词：癌 非小细胞肺 抗药性 肿瘤 受体 表皮生长因子 蛋白激酶抑制剂类 整合素Β1 吉非替尼 

分 类 号：R734.2[医药卫生—肿瘤]