EZH2／STAT3／FoxO1信号通路调控口腔鳞癌EMT相关糖代谢和 “失巢凋亡” 逃逸的分子机制

Abnormal glucose metabolism plays important roles in invasion, metastasis, and“anoikis” in tumor cells. The recent researches show that there is a close link between tumor glucose metabolism and EMT. And EZH2／STAT3／FoxO1 signalling pathway may has essential roles. At present work, we found the mechanism of miR-101-EZH2 axis induces EMT and metastasis mediated by Snail in oral squamous cell carcinoma (OSCC) cells. Thus, we put forward the hypothesis: EZH2／STAT3／FoxO1 pathway may play essential roles in the regulation of EMT related glucose metabolism, inducing of “anoikis”escape, and promoting invasion and metastasis in OSCC. Based on this hypothesis, this research is going to use various advanced techniches, including RNAi, confocal laser scanning microscope,animal PET/CT, and real-time PCR array, to study the regulatory effect of EZH2／STAT3／FoxO1 pathway on glucose and lactic acid levels, mitochondrial Respiratory control (RCR), oxidative stress reactive oxygen species (ROS), and apoptosis in OSCC cells. The aim is to explore the mechanism of EMT related invasion and metastasis in OSCC. These results will provide theoretical basis for therapeutically strategy to prevent and control the invasion and metastasis by targeting EZH2 protein for OSCC patients.

肿瘤异常糖代谢在肿瘤逃逸“失巢凋亡”和侵袭转移中发挥重要作用。最新研究显示，肿瘤糖代谢与EMT密切相关；EZH2／STAT3／FoxO1信号通路可能在肿瘤糖代谢促进EMT中扮演重要角色。本课题组前期研究发现，Snail介导miR-101-EZH2信号轴是诱导口腔鳞癌细胞EMT和转移的重要机制。在此基础上，结合最新研究进展提出科学假设：EZH2／STAT3／FoxO1信号通路在调控口腔鳞癌细胞EMT相关糖代谢、诱导口腔鳞癌逃逸“失巢凋亡”、促进口腔鳞癌侵袭转移中发挥关键作用。围绕此假设，本研究拟采用RNAi、激光共聚焦、小动物PET/CT、芯片等技术和方法，研究EZH2／STAT3／FoxO1信号通路对口腔鳞癌细胞葡萄糖含量、乳酸含量、线粒体呼吸控制率（RCR）、氧化应激活性氧（ROS）、EMT发生和凋亡的调控机制。研究结果将为靶向EZH2信号通路防治口腔鳞癌侵袭转移策略提供理论依据。

肿瘤异常糖代谢在肿瘤逃逸“失巢凋亡”和侵袭转移中发挥重要作用。最新研究显示 ，肿瘤糖代谢与EMT密切相关；EZH2/STAT3/Fox01信号通路可能在肿瘤糖代谢促进EMT中扮演重要角色。本课题组在前期研究的基础上，结合最新研究进展，通过体内体外研究方法，采用慢病毒包装转染、荧光免疫、细胞迁徙实验、细胞周期检测、葡萄糖/乳糖含量检测、裸鼠成瘤实验和活体成像等手段，研究EZH2 / STAT3 / Fox01 信号通路对口腔鳞癌细胞EMT、侵袭转移、和凋亡的调控机制。研究结果示在，在体外实验中，敲除EZH2的实验细胞组较EZH2过表达组和对照组E-cadherin表达上调，STAT3甲基化水平显著增高，细胞转移能力增强；动物实验中，干涉EZH2 / STAT3 / Fox01 信号通路组的裸小鼠移植瘤增长很快，远超对照组。以上结果证实EZH2 / STAT3 / Fox01 信号通路与口腔鳞癌的恶性进程密切相关，在调控口腔鳞癌细胞EMT相关糖代谢、诱导口腔鳞癌逃逸“失巢凋亡”、 促进口腔鳞癌侵袭转移中发挥关键作用。研究结果将为靶向EZfI2信号通路防治口腔鳞癌侵袭转移策略提供理论依据。