[1]刘明,任敦强,郑丽霞,等.TGF-β1介导的上皮-间质转分化在Gefitinib耐药中的作用[J].陆军军医大学学报(原第三军医大学学报),2013,35(15):1558-1561.
 Liu Ming,Ren Dunqiang,Zheng Lixia,et al.Role of TGF-β1-induced epithelial-mesenchymal transition in resistance to gefitinib in non-small cell lung cancer[J].J Amry Med Univ (J Third Mil Med Univ),2013,35(15):1558-1561.
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陆军军医大学学报(原第三军医大学学报)[ISSN:1000-5404/CN:51-1095/R]

卷:
35卷
期数:
2013年第15期
页码:
1558-1561
栏目:
论著
出版日期:
2013-08-15

文章信息/Info

Title:
Role of TGF-β1-induced epithelial-mesenchymal transition in resistance to gefitinib in non-small cell lung cancer
作者:
刘明任敦强郑丽霞于宝丹徐军
广州医科大学附属第一医院呼吸科,广州呼吸疾病研究所,呼吸疾病国家重点实验室;青岛大学医学院附属医院呼吸科
Author(s):
Liu Ming Ren Dunqiang Zheng Lixia Yu Baodan Xu Jun
Department of Respiratory Diseases,Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Disease,  First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, 510120; Department of Respiratory Diseases, Affiliated Hospital of Qingdao Medical College, Qingdao University, Qingdao, Shandong Province, 266003, China
关键词:
肺肿瘤TGF-β1上皮-间质转化表皮细胞生长因子受体耐药
Keywords:
lung neoplasms TGF-β1 epithelial-mesenchymal transition epidermal growth factor receptor resistance
分类号:
R329.24; R734.2; R965
文献标志码:
A
摘要:
目的      调查上皮-间质转化(epithelial-mesenchymal transition, EMT)在非小细胞肺癌(non-small cell lung cancer,NSCLC)患者接受吉非替尼(Gefitinib)治疗反应性中的作用及机制。      方法       突变富集PCR法检测NSCLC患者EGFR 突变状况;免疫组化法检测癌组织中上皮钙粘蛋白(E-cadherin)和纤维连接蛋白(Fibronectin)的表达情况,探讨EMT与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)治疗敏感性的关系。体外选取人肺腺癌细胞系PC9细胞,经TGF-β1反复处理4周,观察细胞形态学变化;MTT检测TGF-β1处理后细胞对Gefitinib敏感性的影响;Western blot验证EMT相关标记蛋白表达变化并检测EGFR信号通路下游蛋白的变化。      结果       43例NSCLC标本中, EGFR 19、21外显子突变率为58.14%(25/43)。具有EGFR基因突变的肿瘤E-cadherin的表达水平显著高于EGFR 野生型(70.00% vs 30.00%, P<0.05)。接受Gefitinib总体有效率为46.51%(20/43),具有E-cadherin阳性表达的患者治疗反应性明显好于Fibronectin阳性的患者(65.00% vs 30.43%,P<0.05)。TGF-β1可诱导PC9细胞向间质型细胞形态转化,上调Fibronectin的表达;与亲本PC9细胞相比,TGF-β1处理的细胞对Gefitinib的敏感性下降(P<0.05);这种敏感性的下降伴随着AKT和STAT3的持续活化。      结论       EMT在EGFR-TKI耐药中发挥着重要作用,TGF-β1诱导的EMT可影响PC9细胞对Gefitinib的敏感性,这种效应可能是通过持续活化AKT和STAT3而发挥作用。
Abstract:
Objective       To clarify the role and mechanism of epithelial-mesenchymal transition (EMT) in the sensitivity of non-small cell lung cancer (NSCLC) patients treated with gefitinib.       Methods      Epidermal growth factor receptor (EGFR) mutations were detected by mutant-enriched PCR assay, and the expression of E-cadherin and fibronectin were evaluated by immunohistochemistry (IHC). Cultured PC9 cells were treated with TGF-β1 for 4 weeks, and the morphological changes were observed by phase-contrast microscopy. MTT assay was used to detect the sensitivity of cells to gefitinib. In addition, the expression of EMT-related marker proteins (E-cadherin and fibronectin) and EGFR downstream signaling molecules (p-ERK, p-AKT and p-STAT3) were assessed by Western blotting.       Results       EGFR gene mutations were identified in 25 of 43 samples (46.51%). The frequency of E-cadherin-positive samples was significantly higher in the samples with EGFR mutants than in those with wild-type EGFR (70.00% vs 30.00%, P<0.05), and the overall response rate to gefitinib was 46.51% (20/43). The treatment responsiveness in the E-cadherin-positive patients was significantly higher than that in the fibronectin-positive patients (65.00% vs 30.43%, P<0.05). TGF-β1 could induce an EMT morphological alteration and up-regulate the expression of fibronectin in PC9 cells. The sensitivity to gefitinib was decreased in the PC9 cells treated with TGF-β1, and the activation of AKT and STAT3 were observed in vitro.       Conclusion       EMT plays an important role in the resistance to EGFR-tyrosine kinase inhibitors (TKIs). Induction of EMT by TGF-β1 may contribute to the decreased efficacy of gefitinib therapy through sustaining activation of AKT and STAT3.

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更新日期/Last Update: 2013-08-05