食管癌受体相互作用蛋白3的核定位及其作用机制研究

Esophageal cancer is one of the most malignant cancers in China. Cellular necrosis is associated with the carcinogenesis, development of cancer and effectiveness of chemotherapy in treatment of esophageal cancer. RIP3 is a key regulator of cell necrosis because of its regulatory function, it became recently a research hot pot. Based on our previous results, we found that the RIP3 was localized in nucleus of esophageal cancer cells. In this study, on the basis of our previous cellular RIP3-overexpression model, we will investigate the molecular mechanism of RIP3 expression in nucleus. We will identify the correlation between the ubiquitination of RIP3 and its nuclear localization. We will explore the biological function of RIP3 expressed in nucleus and its molecular mechanism and role in the development of ESCC. Based on this investigation, we will be able also to discover the important functions and molecular mechanism of RIP3 regulation of other cellular processes in esophageal cancer cells. A better understanding of RIP3 biological functions will be very significant for finding new target, developing new strategy of cancer treatment depending on the regulation of cell necrosis, mobilizing the body's immune system, and inhibiting tumor growth.

食管鳞癌是我国常见恶性肿瘤之一，细胞坏死与食管癌的发生发展及化疗敏感性密切相关，RIP3作为细胞坏死调控的关键分子，成为当前细胞程序化坏死调控研究的热点。我们前期研究发现敲降RIP3降低了食管癌细胞对化疗药物的敏感性,同时发现RIP3蛋白在食管癌细胞的核内定位趋势。本课题拟在我们前期建立的稳定过表达RIP3的食管癌细胞模型的基础上，深入解析RIP3核内定位的分子机制，明确RIP3泛素化修饰与核内定位的相关性，探索泛素化RIP3核内定位的生物学效应及对食管癌化疗敏感性的影响。通过对RIP3蛋白的泛素修饰、核定位及生物学效应的深入研究，将从一个侧面帮助我们揭示RIP3调控细胞生理过程的分子机制，确定RIP3蛋白在核内转录调控的重要生物功能，探讨RIP3蛋白在食管癌发生发展及化疗敏感性的重要作用。

食管鳞癌是我国常见恶性肿瘤，细胞坏死与食管癌的发生发展及化疗敏感性密切相关。前期研究发现，在一些缺失促凋亡蛋白的食管癌细胞和组织中，肿瘤细胞对化疗药物仍具有一定的敏感性。除凋亡外，细胞中还存在由不同的信号通路调控的其他细胞化死亡方式，如细胞程序化坏死、自噬等。其中，细胞坏死调控的关键分子——受体相互作用蛋白3（receptor-interacting protein3，RIP3）在TNFa诱导的细胞坏死信号转导和细胞代谢通路中发挥重要的调控作用。在前期工作基础上，本研究建立了稳定过表达RIP3的食管癌细胞，探索了RIP3表达与细胞化疗敏感性的关系。发现RIPK3调控化疗药物耐药的食管癌细胞发生程序性坏死、发现小分子药物YM155可以诱导RIP3内源缺失的食管癌细胞产生parthanatos样的细胞死亡，以及Stathmin调控食管癌细胞侵袭转移的机制。本项目执行期间，发表标注基金编号的SCI论文5篇，核心期刊5篇；申请国家发明专利1项，专利授权2项；培养研究生4名；获2014年北京市科学技术奖三等奖（排名3）。