死亡蛋白FADD的新功能：上皮-间质转化（EMT）调控及其分子机制研究

Our research team has been long-timely investigating the non-apoptotic biological functions of classical apoptotic protein FADD. Recently we have found several new biological functions and the underlying mechanisms of FADD protein, which have better interpreted the diversity of FADD biological function. Our previous proteomic studies in A549 lung cancer cells indicate that FADD, as a classical death protein, is most likely involved in the epithelial-mesenchymal transition (EMT) process. Also, we have identified a heterogeneous nuclear ribonucleoprotein hnRNP A2/B1 as a novel partner of FADD. FADD deficiency promotes EMT, while FADD and hnRNP A2/B1 double-knockout can reverse the phenotype of EMT. All these results suggest important biological regulation of FADD on tumor cells and this novel function of FADD is probably not due to its apoptotic or death function. This phenotype and detailed mechanism has not been reported up to now. This proposal will use genetically modified cell and animal models of FADD and hnRNP A2/B1 to systematically investigate the role of FADD/hnRNP A2/B1 in EMT and the related mechanisms. This proposal aims to broaden our understanding and knowledge on the biological functions of FADD and EMT. We will also explore the possibility of FADD/hnRNP A2/B1 and its regulation as therapeutic or intervention target for tumor metastasis, and thus provide novel therapeutic target and approach for treatment of cancer.

本课题组长期从事经典凋亡蛋白FADD的非凋亡新生物学功能研究，近年来相继发现了FADD的多种新生物学功能及其机制，较好诠释了FADD生物学功能的多样性。课题组前期的蛋白质组学研究显示：作为经典死亡蛋白的FADD可能参与肿瘤细胞的上皮-间质转化（EMT）过程，并鉴定出核糖核蛋白hnRNP A2/B1作为FADD的一个新相互作用蛋白；FADD缺失促进EMT的发生，而FADD和hnRNP A2/B1共缺失可以逆转肿瘤细胞EMT表型。这些结果提示FADD对肿瘤细胞具有尚未被认识的重要生物学功能。本项目拟采用FADD和hnRNP A2/B1基因改造的细胞和动物模型，系统地研究FADD/hnRNP A2/B1在EMT中的作用及其机制，拓宽对FADD生物学功能和EMT过程的认识和理解，探索将FADD/hnRNP A2/B1及其调控作为肿瘤转移治疗靶点的可能性，为恶性肿瘤的治疗提供新的分子靶点和治疗策略。

FADD是死亡受体介导的凋亡通路中的接头蛋白。近年来的研究发现FADD还参与其它许多非凋亡生物学过程。本课题通过差异蛋白质组学技术，首次揭示FADD调控肿瘤细胞上皮-间质转化（EMT）的新功能并鉴定出核糖核蛋白hnRNP A2/B1为FADD的一个新的相互作用蛋白。研究发现FADD缺失促进EMT的发生，而FADD和hnRNP A2/B1共缺失可以逆转肿瘤细胞EMT表型。进一步的分子机制分析表明，FADD/ hnRNP A2/B1可能通过PKC信号通路参与EMT过程的调控。本课题系统地研究了FADD/hnRNP A2/B1在EMT过程中的作用及其相关机制，拓宽了对FADD生物学功能和EMT过程的认识和理解，探索了将FADD/hnRNP A2/B1及其调控作为肿瘤转移治疗靶点的可能性，为恶性肿瘤的治疗提供新的分子靶点和治疗策略。