HCMV潜伏相关UL138基因诱导胃癌免疫原性细胞死亡的分子机制及其效应

Gastric cancer is one of the high incidence of malignant tumors in our country, but still lacks effective treatment. Human cytomegalovirus (HCMV) may participate in the initiation and development of the neoplastic process. Our previous studies indicated that HCMV infection was implicated in gastric cancer. As well as inducing the apoptosis of gastric cancer cells, Its UL138 gene can also cause Immunogenic cell death (ICD) of gastric cancer cells at the same time. However, its detail mechanisms are still unclear. In this study, we further investigate UL138-related ICD and its molecular mechanism in gastric cancer cells. Firstly, by overexpressing UL138 gene, we observed the biological characteristics and the changes of ICD-related protein in gastric cancer cell dynamically. Based on the in vivo experiments, the biological effects of UL138 gene on the ICD of gastric cancer cells were verified. Then, we screened and identified the key protein which regulate UL138 gene with the methods of protein chip technology. At last, combined with the expression of UL138 and related key protein in gastric cancer, we further analyzed the prognosis of the patients with gastric cancer ICD, which will provide a basis for the follow-up study of tumor immunotherapy. This study will further explore the prevention and treatment of gastric cancer from a new perspective of the relationship between HCMV infection and the ICD of gastric cancer, and provide a new target and the strategy for gastric-tumor-specific immunotherapy.

胃癌是我国高发的恶性肿瘤，但依然缺乏切实有效的治疗措施。人巨细胞病毒（HCMV）与肿瘤的发生发展相关。我们前期数据提示，HCMV感染与胃癌相关，其UL138基因在诱导胃癌细胞凋亡的同时，亦能引起胃癌细胞免疫原性死亡，但具体机制不明。本项目进一步探讨UL138相关胃癌细胞免疫原性死亡效应及其分子机制。通过使胃癌细胞过表达UL138基因，动态观察胃癌细胞生物学特性及免疫原性死亡相关蛋白变化；结合体内实验，分析UL138基因在胃癌细胞免疫原性死亡中相关生物学效应；通过蛋白质组芯片等技术筛选和鉴定UL138基因调控的关键蛋白，并探索其效应机制；结合胃癌组织中UL138及相关关键蛋白表达情况，分析胃癌免疫原性死亡相关预后情况，为后续肿瘤免疫治疗研究提供基础。本研究将从HCMV 感染与胃癌免疫原性细胞死亡相关性这个全新的角度进一步探讨胃癌的防治研究，为胃癌肿瘤特异性免疫治疗提供新的靶点和策略。

胃癌是我国高发的恶性肿瘤，其发病率和死亡率均居我国恶性肿瘤第三位，是严重威胁我国公众生命健康的疾病。虽然，以手术和放疗、化疗为主的胃癌治疗手段有了长足的进步，但这些疗法缺乏肿瘤特异性。随着研究的进展，肿瘤免疫治疗越来越凸显其在肿瘤治疗中的重要作用。目前有研究发现HCMV感染是脑胶质瘤、结肠癌、胃癌等恶性肿瘤发生发展的重要因素，本研究选择HCMV潜伏感染相关基因UL138，体外细胞学功能实验和体内裸鼠皮下瘤模型都验证UL138蛋白表达促进胃癌细胞凋亡。动态观察胃癌细胞生物学特性及免疫原性死亡相关蛋白变化，WB分析发现UL138表达不改变HSP70表达，但刺激胃癌细胞在短时间内表达与免疫原性死亡相关的蛋白。对426例胃癌标本进行免疫组织化学芯片分析发现UL138蛋白表达与免疫指标CD3, CD4,CD8,CD56, CD163呈现共表达关系。进一步通过蛋白质芯片筛选出UL138相互作用蛋白DAXX，研究发现在胃癌细胞中UL138蛋白表达促使DAXX蛋白从细胞核转移到胞浆中，从而引起细胞凋亡，并趋化NK细胞浸润，影响胃癌组织的免疫反应。本研究从HCMV感染影响胃癌组织生物学功能的角度，探讨病毒感染过程中引起的免疫微环境的改变，可能为肿瘤特异性免疫治疗提供新的靶点。