CD146调控EMT过程驱动肺癌细胞“干性”获得致EGFR-TKI耐药后肺癌转移的机制研究

项目名称： CD146调控EMT过程驱动肺癌细胞“干性”获得致EGFR-TKI耐药后肺癌转移的机制研究

项目编号： No.81472835

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张晓菊

作者单位： 郑州大学

项目金额： 64万元

中文摘要： EGFR-TKI耐药是非小细胞肺癌（NSCLC）靶向治疗领域亟待解决的难题之一，目前的机制研究难以完全解释耐药后肿瘤的远处转移。我们前期研究发现：（1）EGFR-TKI耐药过程中CD146及CD44表达均显著上调；（2）EGFR-TKI耐药后肺癌细胞出现EMT；（3）CD146抗体干预后耐药细胞p-AKT表达下调，侵袭力下降。他人研究证明（1）CD146通过非经典Wnt5a信号通路调控细胞迁移；（2）Akt过度活化是EGFR-TKI耐药后的重要代偿机制；因此假设：CD146调控EMT过程并驱动肺癌细胞干性获得，以致耐药后肺癌侵袭转移能力增强？为此拟研究：①CD146靶向治疗能否逆转EMT，下调肺癌细胞干性特征？②CD146介导肺癌细胞侵袭转移的信号通路？③靶向CD146对EGFR-TKI治疗后NSCLC转移的阻断作用；④CD146可作为EGFR-TKI治疗NSCLC患者的新型评估指标。

中文关键词： 非小细胞肺癌；CD146；干性；上皮间皮转化；EGFR-TKI耐药

英文摘要： Resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer (NSCLC) becomes an urgent problem in molecular targeted therapy. We have previously shown that(1) the expression of CD146, in parallel with CD44, a stem-cell surface marker, is up-regulated in the process of EGFR-TKI resistance;(2) epithelial-mesenchymal transition(EMT) is an important mechanism of lung cancer cells which acquire EGFR-TKI resistance;(3) monoclonal antibody against CD146 can block Akt phosphorylation in TKI-resistant lung cancer cells and reduce their invasive potentials. Studies from other groups also revealed that: (1) CD146 regulates cell polarity and migration by combining Wnt5a and activating nonclassic Wnt signaling pathway;(2) aberrant activation of Akt is one of the key compensatory mechanisms which regulate the proliferation of lung cancer cells with acquired EGFR-TKI resistance. Based on these data, we hypothesized that CD146 regulate the EMT process , driving lung cancer cells to gain stemness ,to enhance invasive potentials of those EGFR-TKI resistant lung cancer cells .This study is to investigate: (1) Can CD146 targeted therapy reverse EMT and down-regulate lung cancer cells stemness? (2) through which signaling pathways do CD146 mediate the invasion and metastasis of lung cancer cell? (3) The blocking metastasis role on targeted CD146 of NSCLC after EGFR - TKI treatment;(4) can CD146 be used as a novel marker for evaluating the clinical effect of EGFR-TKI treatment

英文关键词： NSCLC;CD146;stemness;EMT;resistance to EGFR-TKI