核糖体蛋白S6调控非小细胞肺癌增殖的分子机制研究

项目名称： 核糖体蛋白S6调控非小细胞肺癌增殖的分子机制研究

项目编号： No.81501968

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陈勃江

作者单位： 四川大学

项目金额： 18万元

中文摘要： 核糖体蛋白S6（rpS6）是参与蛋白质合成的一种重要核糖体结构蛋白。我们前期发现，rpS6在Ser235/236位点磷酸化（p-rpS6）是非小细胞肺癌（NSCLC）患者不良预后的独立危险因素；沉默rpS6/p-rpS6明显抑制NSCLC细胞增殖；初步分析此过程涉及细胞周期重分布，且与Akt2通路（非Akt1/3）密切相关，但具体作用机制不清楚。本项目拟首先利用NSCLC患者组织标本，分析rpS6/p-rpS6在正常组织到NSCLC形成全过程中的表达，探讨其潜在临床应用价值；利用RNA干扰技术和抑制剂改变rpS6/p-rpS6表达，观察NSCLC细胞体内外增殖活性变化；再从细胞凋亡和细胞周期两方面分析细胞增殖改变的原因；随后筛选和验证参与此过程的rpS6下游靶点，并确立rpS6依赖的Akt2上游信号通路。本项目旨在系统揭示rpS6在NSCLC中的作用，为开发新的NSCLC诊疗靶点提供思路。

中文关键词： 气管；支气管肿瘤；核糖体蛋白S6；增殖；细胞周期；信号通路

英文摘要： Ribosomal protein S6 (rpS6) is an important ribosomal structural protein involved in protein synthesis. Our previous study revealed that the phosphorylation of rpS6 at Ser235/236 (p-rpS6) was an independent risk factor for the poor prognosis in non-small cell lung cancer (NSCLC) patients. Additionally, silence of rpS6/p-rpS6 significantly inhibited the proliferation of NSCLC cells, which was preliminary related to the cell cycle redistribution and the regulation of Akt2 signaling pathway, rather than Akt1 or Akt3. However, the specific mechanism was still unclear. In the current study, the expression of rpS6/p-rpS6 in nomal, hyperplasia, squamous metaplasia, atypical adenomatous hyperplasia lung tissues and NSCLC will be detected to explore their potential clinical value. And then the expression of rpS6/p-rpS6 will be changed using RNA interference or specific inhibitors to observe the NSCLC cells proliferation both in vitro and in vivo, followed by which the alteration of cell cycle and cell apoptosis will be detected to explore its underlying mechanism. Furthermore, downstream targets and Akt2 upstream signaling pathway will be investigated as well. This study aims to fully clarify the effects and molecular mechanisms of rpS6 in NSCLC, providing a new target for the diagnosis and treatment of NSCLC.

英文关键词： Trachea; bronchus cancer;Ribosomal protein S6 ;Proliferation;Cell cycle;Signaling pathway