整合素β#20449;号通路在非小细胞肺癌EGFR TKI耐药中的作用

项目名称： 整合素β#20449;号通路在非小细胞肺癌EGFR TKI耐药中的作用

项目编号： No.30873023

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 周彩存

作者单位： 同济大学

项目金额： 30万元

中文摘要： 表皮生长因子受体酪氨酸激酶小分子抑制剂（EGFR TKI）在晚期非小细胞肺癌治疗中发挥重要作用，耐药性限制其临床应用，耐药机制尚未阐明。项目组发现:获得性耐药非小细胞肺癌的细胞株整合素β#34920;达上调,抑制整合素β#21487;恢复耐药非小细胞肺癌细胞株对EGFR TKI的敏感性。通过裸鼠移植瘤模型的体内实验也证实，整合素β#39640;表达是EGFR TKI耐药的一个重要机制。另外，体内外实验均证明，整合素β#21644;c-Met、EGFR、 EMT间存在密切的交互作用，这些交互作用参与了整合素β#30456;关的吉非替尼耐药，这为肺癌和其它恶性肿瘤的治疗提供了新的靶点，开辟了新的领域。本研究还应用Agilent human miRNA芯片检测了吉非替尼耐药细胞株中microRNA的表达谱特征，分析显示miR-214和miR-21表达显著增高，进一步验证说明这两者可能参与EGFR-TKI耐药。

中文关键词： 非小细胞肺癌; 整合素βEGFR TKI;耐药;miRNA

英文摘要： Small molecule tyrosine kinase inhibitors of Epidermal growth factor receptor (EGFR TKI) have been used in clinical treatment of advanced non-small cell lung cancer. Resistance of cancer cells to such agents limits their clinical application and the mechanisms are still unclear.We have found that integrin βis increased in non-small cell lung cancer cells with acquired resistance to EGFR TKI. Inhibition of integrin βcan recover EGFR TKI sensitivity. It also has been confirmed that overexpression of integrin βis an important mechanism of EGFR TKI resistance in vivo. There are crosstalks between integrin βand c-Met, EGFR, EMT and they involved in integrin β related resistance to gefitinib. It will provide new target and idea for the treatment of lung cancer and even other malignant tumors.We also analyzed the microRNA expression profiling of gefitinib-resistant cell line using Agilent human miRNA microarray. The results showed that the expression of miR-214 and miR-21 were significantly increased and the further results suggested that they may be involved in EGFR-TKI resistance.

英文关键词： non-small cell lung cancer; integrin βEGFR TKI;resistance;miRNA