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上皮-间质转化和胰岛素样生长因子Ⅰ型受体在非小细胞肺癌EGFR-TKIs获得性耐药中的作用
         
The role of epithelial-mesenchymal transition and insulin-like growth factorⅠreceptor in acquired resistance to epidermal growth factor-tyrosine kinase inhibitors in non-small cell lung cancer

摘    要
目的:探讨上皮-间质转化(epithelial-mesenchymal transition,EMT)和胰岛素样生长因子Ⅰ型受体(insulin-like growth factorⅠreceptor,IGF-1R)在非小细胞肺癌(non-smallcelllungcancer,NSCLC)对表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)获得性耐药中的作用。方法:选用EGFR基因突变型和野生型的人肺腺癌细胞PC-9和H460,分别用吉非替尼和厄洛替尼将其诱导成耐药的PC-9/ZD和H460/ER细胞。MTT法检测各组细胞的增殖情况,划痕实验及Transwell侵袭实验检测细胞迁移和侵袭能力,蛋白质印迹法和RT-PCR法分别检测IGF-1R及EGFR信号通路分子及EMT相关分子的蛋白和mRNA表达。结果:PC-9/ZD和H460/ER为EGFR-TKI获得性耐药细胞,分别对吉非替尼和厄洛替尼的敏感性显著下降,差异有统计学意义(P<0.05)。与PC-9和H460细胞相比,耐药的PC-9/ZD和H460/ER细胞形态呈现间质细胞表型,细胞侵袭和迁移能力增加(P<0.05)。PC-9/ZD和H460/ER细胞中间质标志分子vimentin的mRNA和蛋白表达量均显著增加(P<0.05),PC-9/ZD细胞的E-cadherin表达量显著减少(P<0.05)。与PC-9和H460细胞相比,PC-9/ZD与H460/ER细胞的IGF-1R及其磷酸化蛋白表达量显著增加(P<0.05),AKT和ERK磷酸化水平明显上调(P<0.05)。PC-9/ZD细胞的EGFR磷酸化水平与PC-9细胞相比未见明显差异(P>0.05),而H460/ER细胞的EGFR磷酸化水平较H460细胞显著降低(P<0.05)。结论:EGFR突变型PC-9细胞和野生型H460细胞的获得性耐药细胞中均发生了EMT,并且IGF-1R信号蛋白表达增多,提示EMT及IGF-1R信号转导通路均可能在NSCLC的EGFR-TKIs获得性耐药中起重要作用。
标    签   非小细胞肺   抗药性   肿瘤   蛋白激酶抑制剂   胰岛素样生长因子Ⅰ   上皮-间质转化   表皮生长因子受体-酪氨酸激酶抑制剂   Carcinoma   non-small cell lung   Drug resistance   neoplasm   Protein kinase inhibitors   Insulin-like growth factorⅠ   Epithelial-mesenchymal transition   EGFR-TKIs  
 
Abstract
Objective:To investigate the role of EMT (epithelial-mesenchymal transition) and IGF- 1R (insulin-like growth factor Ⅰ receptor) in acquired resistance to EGFR-TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) in NSCLC (non-small cell lung cancer). Methods:TheEGFR mutant human lung adenocarcinoma PC-9 cell line and theEGFR wild-type H460 cell line were used to generate gefitinib-resistant PC-9 cells (named as PC-9/ZD cells) and erlotinib-resistant cells (named as H460/ER cells), respectively. MTT assay was used to measure the cell proliferation of PC9, PC-9/ZD, H460 and H460/ER cells. Wound-healing assay and Transwell assay were used to determine the migration and invasion capabilities of the cells. The protein and mRNA expressions of E-cadherin, vimentin,EGFR, ERK (extracellular signal-regulated kinase), AKT (protein kinase B) and IGF-1R were determined by Western blotting and RT-PCR (reverse transcription PCR), respectively. Results:Both PC-9/ZD and H460/ER cells acquired resistance to EGFR-TKIs which was to say that the sensitivities to gefitinib and erlotinib in PC-9/ ZD and H460/ER cells were significantly decreased, respectively (P<0.05). Compared with PC-9 and H460 cells, the PC-9/ZD and H460/ER cells displayed mesenchymal phenotypes, and their capabilities of invasion and migration were enhanced (P<0.05). The expression of mesenchymal cell marker vimentin was increased in both PC-9/ZD and H460/ER cells (P<0.05), and the expression of E-cadherin was decreased in PC-9/ZD cells (P<0.05). The expressions of IGF-1R and its phosphorylated form in both PC-9/ZD and H460/ER cells were significantly increased (P<0.05) as compared with those in the PC-9 and H460 cells, accompanied by up-regulation of phosphorylation levels of AKT and ERK (P<0.05). No significant difference was found in phosphorylation level ofEGFR between PC-9 and PC-9/ZD cells (P<0.05), while the phosphorylation level ofEGFR was significantly decreased in H460/ER cells as compared with that in H460 cells (P<0.05). Conclusion:The EMT inEGFR mutant gefitinib-resistant PC-9/ZD cells and theEGFR wild-type erlotinib-resistant H460/ER cells was accompanied by a increase in protein expression of IGF-1R, which suggests EMT and IGF-1R signal transduction may play an important role in acquired resistance to EGFR-TKIs in NSCLC cells.

中图分类号 R734.2   DOI 10.3781/j.issn.1000-7431.2013.02.001

 
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所属栏目 基础研究

基金项目 国家自然科学基金资助项目(编号:81172225)

收稿日期 2012/11/2

修改稿日期 2013/1/16

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引用该论文: WANG Jin-jing,ZHANG Wei-min,CHEN Bei,LIN Jian-guang. The role of epithelial-mesenchymal transition and insulin-like growth factorⅠreceptor in acquired resistance to epidermal growth factor-tyrosine kinase inhibitors in non-small cell lung cancer[J]. Tumor, 2013, 33(2): 103~110
王津京,张为民,陈蓓,林建光. 上皮-间质转化和胰岛素样生长因子Ⅰ型受体在非小细胞肺癌EGFR-TKIs获得性耐药中的作用[J]. 肿瘤, 2013, 33(2): 103~110


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