DNA病毒致瘤蛋白通过与PERK互作促进肿瘤发生发展的机制研究

About 12% human cancers are closely associated with viral infection such as nasopharyngeal carcinoma and cervical carcinoma. LMP1 and E7 are two major oncoproteins coded by EBV and HPV respectively, which can promote cell proliferation and survival. PERK, a serine/ threonine kinase located in ER, mediates ER stress and increases expression of antioxidant genes through activation of Nrf2. Our studies indicated that LMP1 and E7 can inhibit PERK phosphorylation, leading to increase of cellular ROS. Therefore, we hypothesize that DNA virus oncoproteins LMP1 and E7 increase oxidative stress through inhibiting PERK to promote genome instability and cell proliferation. This project will clarify the mechanism by which DNA virus oncoproteins regulates ER stress and oxidative stress in the cellular, clinical sample and animal level. In this study, we will further investigate how DNA virus oncoproteins inhibit PERK, wherther the inhibituion of PERK increase cellular oxidant stress. More importantiy, we aim to address wherther the inhibition of PERK by DNA virus oncoproteins regulates tumor progression. This study will be helpful to understand the oncogenic mechanism of LMP1 and E7 and provide experimental basis for targeting LMP1 and E7 for treating nasopharyngeal carcinoma and cervical carcinoma.

人类肿瘤中约有12%与病毒密切相关，如鼻咽癌和宫颈癌等。LMP1和E7分别是EBV和HPV编码的致瘤蛋白，与相关肿瘤发生发展密切相关。PERK定位于内质网，是介导内质网压力的丝/苏氨酸激酶，通过激活转录因子Nrf2促进抗氧化基因表达。我们前期发现LMP1和E7能够抑制 PERK磷酸化，且减弱Nrf2的转录活性，增加细胞ROS。由此我们提出，DNA病毒致瘤蛋白LMP1和 E7通过抑制PERK活性增强细胞氧化压力，导致基因组不稳定，从而促进肿瘤发展。本项目拟在细胞、动物、临床样本三个层面上研究（1）DNA病毒致瘤蛋白抑制PERK的分子机制；（2） DNA病毒致瘤蛋白通过 PERK对氧化压力的调控机制；（3）DNA病毒致瘤蛋白通过抑制PERK对肿瘤生长的影响。本项研究将有助于进一步理解DNA病毒致瘤蛋白的致瘤机理，为鼻咽癌和宫颈癌的新药物靶点提供理论依据。

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