瘤蛋白LMP1通过EGFR和PKM2相互作用调控鼻咽肿瘤干细胞标志物的分子机制

Pyruvate kinase M2 (PKM2) is a critical metabolic enzyme of Warburg effect that embodies metabolic reprogramming in cancer cells. Recent findings demonstrate that reprogramming in stem cells is closely associated with metabolic reprogramming. Our previous findings show that latent membrane protein 1 (LMP1) encoded by Epstein-Barr virus may promote the nuclear translocation of epidermal growth factor receptor (EGFR) in nasopharyngeal carcinoma, in turn, the nuclear EGFR affect cell proliferation and cell cycle progression lonely or interacting with other protein. Recently we found that LMP1 regulated the colocaliztion of EGFR and PKM2 in the nucleus and LMP1 could promote glycolysis in nasopharyngeal carcinoma cells. Based on these, we will use nasopharyngeal carcinoma cells as a model to investigate the process that the nuclear translocation of the intact complex of EGFR and PKM2 triggered by LMP1 and their binding with transcriptional activation related histone to induce the expression of stem cells markers, thus resulting in promoting glycolysis.

Warburg效应是肿瘤细胞代谢重编程的主要特征，丙酮酸激酶(PKM2)是Warburg效应的重要代谢酶。最新研究表明干细胞的重编程与代谢重编程密切相关，我们的前期研究发现EBV编码的瘤蛋白LMP1可促进EGFR核移位，单独或与其他蛋白相互作用影响鼻咽癌细胞增殖和细胞周期行进。新近我们发现LMP1可调控EGFR和PKM2共定位于鼻咽癌细胞核内, 促进细胞糖酵解。基于此，申请者拟以鼻咽癌为研究模型，阐明癌蛋白LMP1调控EGFR和PKM2入核发生相互作用，直接与转录活化相关组蛋白H3结合，使靶基因启动子区H3乙酰化水平增加，导致鼻咽癌干细胞标志物基因的表达水平增加，进而促进糖酵解的分子机制。

放射治疗已成为肿瘤综合治疗的重要手段，有肿瘤干细胞特征的细胞群比普通肿瘤细胞具有更明显的放疗抵抗效应，是造成许多晚期肿瘤患者对放化疗耐受和复发的重要原因。丙酮酸激酶PKM2除了发挥代谢关键酶的作用外，也可作为一种蛋白激酶以非代谢功能的方式，通过生长因子信号通路的活化入核激活靶基因。我们前期工作基础已证实，随着放射剂量的增加EGFR表达水平增加，且EGFR和PKM2存在共定位。基于此，本项目拟以放疗抵抗细胞株为研究模型，阐明EGFR和PKM2入核发生相互作用，直接转录活化肿瘤干细胞标志物基因启动子区，参与调节肿瘤干细胞特性及侵袭转移中的具体机制。