肿瘤细胞非凋亡的细胞程序死亡调控与治疗敏感性研究

During the course of evolution, cells develop a set of intricate cell death regulatory mechanisms to balance life and death. In addition to apoptosis, there are several non-apoptotic forms of programmed cell death in multicellular organisms, such as autophagy and necroptosis. Chemotherapeutic drugs often kill cancer cells by inducing apoptosis, and the mechanisms of chemotherapy-induced apoptosis are well characterized. However, the regulatory mechanisms and functional roles of non-apoptotic cell death in cancer chemotherapy are not well understood.Based on previous productive collaboration, the investigators propose to study how defective apoptosis regulation in cancer cells leads to activation of non-apoptotic cell death including autophagy and necroptosis. They will use proteomics and other high-throughput approaches to characterize protein-protein interactions, in particular, complex formation by caspases and RIP,in order to understand how autophagy and necroptosis are triggered when apoptosis is blocked in cancer cells. The project will provide new insight on how caspases regulate autophagy and necroptosis in determining chemo sensitivity, and identify novel molecular targets for improving chemo sensitivity and for overcoming resistance to chemotherapy.

食管癌变是逐步从炎症向肿瘤恶性转化的疾病过程，食管上皮经历炎症、不典型增生、原位癌和浸润性癌等炎癌转化和系列基因突变的积累过程。化疗是进展期肿瘤患者和转移性疾病的标准治疗手段，但多数患者反应不佳。顺铂等常见化疗药可引起细胞程序性坏死。炎癌转变和程序性坏死的关键分子受体相互作用蛋白激酶3（RIP3），参与化疗药引起的细胞坏死过程。本研究以caspases/RIP复合体为节点，利用多种来源的转录和蛋白质组数据，评价RIP3在正常人体组织和常见肿瘤中的表达模式；采用系统优化的定量、深度蛋白质组分析策略，在敲降RIP3的食管癌细胞中分析受RIP3调控的蛋白，建立RIP3调控顺铂耐药模型，认识Caspase/RIP复合体与细胞坏死和凋亡间调控的分子机理；选择1-2个RIP3的下游关键分子，通过异种移植瘤和模拟食管炎癌转变全过程的4NQO小鼠食管鳞癌模型，评价RIP3下游关键分子抑制剂的顺铂疗效。

食管癌变是逐步从炎症向肿瘤恶性转化的疾病过程，食管上皮经历炎症、不典型增生、原位癌和浸润性癌等炎癌转化和系列基因突变的积累过程。化疗是进展期肿瘤患者和转移性疾病的标准治疗手段，但多数患者反应不佳。顺铂等常见化疗药可引起细胞程序性坏死。炎癌转变和程序性坏死的关键分子受体相互作用蛋白激酶3（receptor interacted protein 3, RIP3），参与化疗药引起的细胞坏死过程。本研究以Caspases/RIP复合体为节点，利用多种来源的转录和蛋白质组数据，评价了RIP3在正常人体组织和常见肿瘤中的表达模式；采用系统优化的定量、深度蛋白质组分析策略，在敲降RIP3的食管癌细胞中分析了受RIP3调控的蛋白，建立RIP3调控顺铂耐药模型，探讨了Caspase/RIP复合体与细胞坏死和凋亡间调控的分子机理。发现RIP3是一种新的食管癌化疗疗效预测标志物，HSP90抑制剂和顺铂联用可以提高顺铂的化疗疗效。发现新型微管去稳定剂SL-3-19，SL-1-73和IG-105等小分子微管靶向药物能显著抑制食管癌细胞增殖，其中SL-3-19可能成为未来食管癌治疗的有效候选药物。..课题完成了预期考核指标，发表SCI论文5篇，国内核心期刊论文1篇。投稿会议摘要10篇，申请和授权国家发明专利共两项。培养硕士研究生5名和博士研究生4名。