基于乏营养环境下Nrf2促进非小细胞肺癌侵袭转移的机制研究

项目名称： 基于乏营养环境下Nrf2促进非小细胞肺癌侵袭转移的机制研究

项目编号： No.81501987

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 胡婷华

作者单位： 西安交通大学

项目金额： 18万元

中文摘要： 乏营养环境下活性氧（ROS）堆积可致细胞损伤。而高ROS条件下非小细胞肺癌（NSCLC）仍生长迅速并发生侵袭转移，其机制尚未明确。抗氧化应激关键转录因子NF-E2相关因子2（Nrf2）可负向调控ROS水平，对抗细胞损伤；我们前期研究发现，Nrf2表达与NSCLC患者淋巴结浸润及远处转移密切相关，且Nrf2与上皮-间质转化（EMT）相关标志物及趋化因子受体CXCR4在NSCLC组织中的表达呈正相关。由此推测：乏营养环境下ROS积累可诱导Nrf2异常高表达，其对抗细胞损伤的同时激活SDF-1/CXCR4通路，促进NSCLC侵袭转移。本研究拟通过慢病毒转染双向调节Nrf2的表达，体外模拟肿瘤乏营养环境，建立裸鼠原位及转移瘤模型，采用小动物活体成像和免疫组化等方法，从组织、细胞和分子水平探究Nrf2在肿瘤乏营养微环境下促进NSCLC侵袭转移行为的调控机制，为NSCLC恶性进展的防治提供新思路。

中文关键词： 肺肿瘤；活性氧；NF-E2相关因子2；SDF-1/CXCR4；侵袭转移

英文摘要： Reactive oxygen species (ROS) accumulation can cause cellular injury under the nutrient starvation environment. However, non-small cell lung cancer even grow quickly and occur invasion and metastasis under high ROS levels. The mechanism is still unknown. Studies have shown that NF-E2 related factor 2 (Nrf2), the key transcription factor of anti-oxidative stress system, can inhibit the intracellular ROS levels effectively, and be against cell damage. Our previous researches showed that the level of Nrf2 was correlated with lymph node metastasis and distant metastasis positively. Moreover, the expression of Nrf2 was positively related with the expression of Epithelial-Mesenchymal Transition (EMT)-relative markers and CXCR4 in NSCLC tissues. We speculate that ROS accumulation can induce Nrf2 high-expression abnormally, and Nrf2 can promote the invasion and metastasis of NSCLC by activation of the SDF-1/CXCR4 signaling pathway. This research regulates the expression of Nrf2 through lenti-viral transfection, and simulates oxygen stress state of tumor microenvironment in vitro. In addition, fluorescence imaging system in vivo and immunohistochemistry are used to observe tumor occurrence and development trends in orthotopic transplantation and metastatic model of nude mice. At last, we explore the role and mechanism of Nrf2 in the invasion and metastasis of NSCLC under the nutrient starvation environment from the level of histology, cytology and molecular biology, and provide new evidence for the prevention and control of the malignant progression of NSCLC.

英文关键词： Non-small cell lung cancer;ROS;Nrf2;SDF-1/CXCR4;invasion and metastasis