RIP1/RIP3调控非小细胞肺癌细胞程序性坏死在大分割放疗中的作用及机制研究

项目名称： RIP1/RIP3调控非小细胞肺癌细胞程序性坏死在大分割放疗中的作用及机制研究

项目编号： No.81472797

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： 袁智勇

作者单位： 天津医科大学

项目金额： 72万元

中文摘要： 大分割放疗（HFRT）治疗早期非小细胞肺癌（NSCLC）取得令人瞩目的疗效，但仍有患者存在放疗抗拒，机制尚未阐明。结合文献及工作基础表明：肿瘤细胞凋亡在放疗中发挥重要作用；当大于一定分割剂量时，肿瘤细胞的死亡方式主要表现为坏死；细胞坏死是由RIP1/RIP3调控的程序化过程，即程序性坏死。本课题组前期研究表明：RIP3的表达在NSCLC细胞系及组织中存在显著差异，干扰RIP1/RIP3表达及采用激酶抑制剂可显著降低细胞坏死率并提高克隆形成率。据此推测：RIP1/RIP3调控肿瘤细胞程序性坏死可能是大分割放疗疗效个体化差异的核心机制。本项目拟从分子、细胞、整体动物及患者四个水平，以RIP1/RIP3调控肿瘤细胞程序性坏死在HFRT中的作用为研究主线，对调控细胞命运的关键分子靶点进行系统研究，通过本课题开展，将为临床优化HFRT个体化治疗方案提供新思路、新靶点，具有重要的理论意义及应用前景。

中文关键词： C05_气管；支气管；肺肿瘤；大分割放疗；程序性坏死；受体交互作用蛋白1/受体交互作用蛋白3；肿瘤免疫

英文摘要： Although hypofractionated radiotherapy (HFRT) in the treatment of early-stage non-small cell lung cancer (NSCLC) achieved a remarkable effect, there are still radiation resistance in some patients with unknown mechanism. Previous studies demonstrated that cell apoptosis may play an important role in cancer radiotherapy based on current evidence, and the death type of cancer cell mainly showed necrosis when a single dose was greater than a certain dose. Recent studies showed that cellular necrosis is not an accidental event, but is a programmed process regulated by reception interaction protein 1(RIP1)/RIP3, which was named cellular necroptosis. In vitro and in vivo data of our group showed that the expression levels of RIP3 were significantly different in NSCLC cells and patients histopathology, and RIP1/RIP3 interference and kinase inhibitor could alleviate cell necrosis rate and improve cell cloning information after HFRT, suggesting that necroptosis regulated by RIP1/RIP3 is among the mechanism of individual difference after HFRT. Therefore,this project will utilize different cell lines, mice model, and patients of NSCLC to investigate the role and molecular mechanism of RIP1/RIP3 induced cancer cell necroptosis after HFRT. This study will provide new idea and target for HFRT personalized therapy, with important theoretic contribution and promising future of application.

英文关键词： Non-small cell lung cancer;hypofractionated radiotherapy;Necroptosis;Reception interaction protein 1/reception interaction protein 3;Tumor immunity