癌蛋白HBXIP激活Nrf2-ARE调控乳腺癌生长的作用及分子机制研究

Keap1-Nrf2-ARE信号通路是细胞抗氧化机制中的重要通路。我们前期研究发现癌蛋白HBXIP在乳腺癌中与Nrf2表达正相关，并可与氧化应激感受器Keap1蛋白直接结合，激活抗氧化应激通路。生物信息学发现HBXIP启动子区含抗氧化应激反应元件ARE，其转录受Nrf2调控。迄今肿瘤细胞通过HBXIP激活Nrf2-ARE通路调控乳腺癌生长的作用及分子机制尚不清楚。本项目拟从分子、细胞、组织和动物等层面深入探讨HBXIP调控抗氧化应激和乳腺癌生长的作用及分子机制；阐明HBXIP通过其GLNLG基序与Keap1竞争性结合并激活Nrf2；确定Nrf2可结合HBXIP启动子ARE，并调控其表达；探明HBXIP-Nrf2在肿瘤细胞中形成环式正反馈调节机制，以及此机制在肿瘤细胞抗氧化应激及乳腺癌生长中的重要作用。本研究将提供癌蛋白HBXIP作为细胞抗氧化应激的关键调节因子促进肿瘤生长的新机制。

The Keap1-Nrf2-Keap1 system is currently recognized as one of the main cellular defense mechanisms against oxidative. Our previous study showed that the expression level of oncoprotein hepatitis B X-interacting protein (HBXIP) was positively related with Nrf2 in breast cancer tissues and cells. HBXIP interacted Keap1, resulting in stabilization of Nrf2. Bioinformatics showed there was an antioxidant reactive element in regulatory region of HBXIP promoter. However，The mechanism of HBXIP activation Nrf2-ARE and regulation ROS level and tumor growth remains unclear. In this project, we will further explore the role and mechanism of HBXIP, as an ROS regulator, in Nrf2-ARE pathway activation and tumor growth promotion. The main contents are as follows: identify that HBXIP shares with Nrf2 a highly conserved DLG-type Keap1 binding motif (GLNLG motif) and can effectively compete with Nrf2 for keap1 binding, which promotes Nrf2 accumulation and function in the nucleus and lowers the cellular reactive oxygen; clearly investigate the effect of Nrf2 binding on ARE-HBXIP, and regulating HBXIP expression; determine the mechanism of positive feedback regulation between HBXIP and Nrf2 on promoting tumor growth. This study will provide a novel mechanism by which HBXIP as key ROS regulator is able to activate Nrf2-ARE pathway to promote tumor growth.