抑癌基因MIIP加速EGFR蛋白质降解并抑制肺癌细胞生长的分子机制

项目名称： 抑癌基因MIIP加速EGFR蛋白质降解并抑制肺癌细胞生长的分子机制

项目编号： No.81201843

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2

项目作者： 文静

作者单位： 中山大学

项目金额： 23万元

中文摘要： 表皮生长因子受体EGFR介导的信号通路是促进肿瘤生长的重要因素，许多肿瘤存在EGFR过表达。细胞EGFR蛋白水平受其降解速度影响。转移和侵袭抑制蛋白MIIP可抑制肿瘤生长，但机制未完全明确。前期研究中，我们发现MIIP高表达可降低非小细胞肺癌中野生型EGFR蛋白质表达并抑制细胞生长；且MIIP促进新生未成熟及成熟野生型EGFR蛋白质降解。据此推测MIIP可能通过影响EGFR成熟及降解的关键调控分子，加速野生型EGFR蛋白质降解，减少生长信号通路激活。我们将通过细胞转染、蛋白质脉冲追踪实验、免疫共沉淀、免疫荧光等方法，观察MIIP依赖于野生型EGFR表达的对非小细胞肺癌的生长调控；探索MIIP影响野生型EGFR蛋白质成熟转运并加速其降解的机制。我们的研究将揭示MIIP发挥抑癌基因功能的机制，明确野生型EGFR蛋白质降解的调控分子，为非小细胞肺癌治疗提供靶向突变EGFR之外的新理论和新靶点。

中文关键词： 转移与侵袭抑制蛋白；表皮生长因子受体；蛋白质降解；非小细胞肺癌；

英文摘要： Epidermal growth factor receptor (EGFR) and its downstream signaling are key regulators of tumor cell growth, and overexpression of EGFR is commonly observed in various types of cancers. Protein turnover is an important factor to determine the EGFR protein expression level. Migration and invasion inhibitory protein (MIIP) was found to inhibit cancer cell growth. However, the underlying mechanisms were not fully understood. In our previous study, we found that overexpression of MIIP reduced the intracellular steady level of wild-type EGFR protein in non-small cell lung cancer cells and inhibited cell growth. This finding was further validated by pulse-chase experiments showing that MIIP accelerated both immature and mature wild-type EGFR protein degradation. It is hypothesized that MIIP might affect molecules which playing significant roles in wild-type EGFR protein maturation and degradation, so as to accelerate wild-type EGFR protein degradation, decrease EGFR and downstream signaling activation and inhibit cancer cell growth. In this study, we plan to determine whether the role of MIIP in cell growth inhibition is EGFR-expression dependent, amd explore the role of MIIP in regulating wild-type EGFR protein maturation, transport and degradation by employing techniques such as cell transfection, protein pulse-ch

英文关键词： migration and invasion inhibitory protein；epidermal growth factor receptor；protein degradation；non-small cell lung cancer；