Wnt-Notch和Wnt-ERBB信号通路调控NSCLC上皮间质转化和耐药的机制研究

项目名称： Wnt-Notch和Wnt-ERBB信号通路调控NSCLC上皮间质转化和耐药的机制研究

项目编号： No.81201666

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 贾佳

作者单位： 上海生物信息技术研究中心

项目金额： 23万元

中文摘要： 分子靶向药物吉非替尼在EGFR激酶受体突变的晚期NSCLC患者中显示了显著的疗效。由于晚期肺癌肿瘤生物学行为的多样性，患者最终都会不可避免地出现药物抗药性，从而导致治疗失败和疾病的恶化，系统研究其分子机制是目前临床亟待解决的问题。我们前期研究表明上皮细胞间质化转化（EMT）是诱导NSCLC肿瘤细胞耐药特性出现的分子基础。Wnt/βcatenin信号可能与Notch和ERBB通路形成复杂的交互网络，调控EMT依赖的原发和继发性耐药。在此基础上，我们拟通过扰动Wnt/β-catenin信号通路及其靶基因Notch2和AREG的表达，观察其对细胞形态和周期、细胞增殖和侵袭能力以及吉非替尼药物敏感性的影响，探索Wnt信号通过TCF4/LEF调控Notch2和AREG基因表达的分子机制，验证Notch2及AREG基因/蛋白表达预测吉非替尼的临床意义和价值，发展早期诊断和预测药物耐药风险的分子标记物。

中文关键词： Wnt信号通路；Notch信号通路；STAT信号通路；上皮细胞间充质转化；非小细胞肺癌

英文摘要： Significant improvements in the outcome of non-small cell lung carcinoma (NSCLC) have been reported in patients treated with the epidermal growth factor receptor (EGFR) inhibitors(EGFR-TKIs). However, EGFR-TKIs) elicit markedly different clinical response rates due to differences in drug bypass signaling as well as genetic variations of drug target and downstream drug-resistant genes. Less than 50% patient EGFR-TKIs response can be accurately predicted by the current developed drug response biomarkers. It is crucial to identify the novel mechanisms involved in the EGFR-TKIs resistance. Cancer cells that change from stationary cells (epithelial) that line organs into mobile mesenchymal cells become more invasive, resistant to treatment and are associated with metastasis and stem cell characteristics. In our previous study, we analyzed the gene expression of 54 non-small cell lung cancer lines and find sets of genes involved in epithelial-to-mesenchymal transition (EMT), Notch and ERBB signaling. Little is known about Notch and ERBB signaling in EMT dependent drug resistant. Based on these observations and established experimental systems, we expect to further evaluate the importance of Notch and ERBB signaling in epithelial and mesenchymal NSCLC models. In the current application ,we extend our hypothesis as foll

英文关键词： Wnt signaling pathway；Notch signaling pathway；STAT signaling pathway；Epithelial mesenchymal transition；Non-small cell lung cancer