HCMV基因在胃癌组织中表达的筛选验证及分子机制

Gastric cancer is the high incidence of malignant tumors in our country, but its etiology and pathogenesis has not been fully elucidated. Human cytomegalovirus (HCMV) establishes a life-long latent infection in the majority of human population worldwide. Emerging evidences suggest that HCMV infection may act as a potential tumor promoter and participate in the initiation and development of the neoplastic process. Our previous studies indicated that HCMV infection was implicated in gastrc cancer. However its detail mechanism is unclear. In this study, we further investigate gastric cancer-related HCMV candidate genes and their effect and mechnism in the pathogenesis of gastric cancer. Firstly，deep sequencing of transcription profiles combined with the methods of RT-PCR and in situ hybridization were used to screen and identify the HCMV genes expressed specifically in the tumor tissues of gastric cancer. Based on the analysis of the relationship between the expression of HCMV genes and the clinicopathological features of gastric cancer, the influence of HCMV genes in cell biological characteristics of gastric cancer cell will further be investigated. Combined with animal experiment of gastric carcinoma transplanted tumor model in vivo， the biology effect of gastric cancer-related HCMV candidate genes will be demonstrated. To clarify the molecular mechanism of gastric cancer-related HCMV genes, key target protein regulated by HCMV genes will be further screened and identified by proteomics technology combined the immune co-precipitation method. In this study, from the point of HCMV infection, we put a new light on the pathogenesis of gastric cancer, which will provide new targets and strategies for the prevention and control of gastric cancer.

胃癌是我国高发的恶性肿瘤，但病因及发病机制尚未完全阐明。人巨细胞病毒（HCMV）可因潜伏感染而使多数人群长期携带，并可作为一种促癌因素与肿瘤的发生与发展相关。我们前期数据提示，HCMV感染与胃癌有关，但具体分子机制不明。本项目进一步探讨与胃癌相关的HCMV基因表达及致病机制。通过基因表达谱深度测序结合RT-PCR和原位杂交等技术，筛选和鉴定胃癌肿瘤组织中特异表达的HCMV相关基因；在分析目标HCMV基因表达与胃癌临床病理特征相关性的基础上，研究HCMV基因对胃癌细胞生物学特性影响，结合胃癌移植瘤动物模型体内实验，分析胃癌相关HCMV基因的生物学效应；通过蛋白质组学结合免疫共沉淀等技术筛选和鉴定HCMV基因调控的关键蛋白，并探索其效应机制。本研究将从HCMV感染与胃癌发生与发展关系这个全新的角度进一步探讨胃癌的发病机制，为胃癌防治提供新的靶点和策略。

病原－宿主互作是病原体感染诱发肿瘤重要机制，其作用机制是目前研究的热点。人巨细胞病毒（HCMV）可因潜伏感染而使多数人群长期携带病毒。近来的研究提示，HCMV作为一种促癌因素与肿瘤的发生发展相关，但与我国高发的胃癌关系及机制尚未阐明。本项目拟在前期研究的基础上，进一步深入探讨HCMV感染与胃癌发生的相关性及致病机制。本项目利用TCGA数据库的胃癌RNA_seq数据，结合多中心大样本的胃癌标本的病毒基因组PCR检测和免疫组化检测，临床水平分析HCMV感染与胃癌的关系；同时，在细胞水平分析HCMV感染对胃癌细胞生物学特性的影响，明确HCMV感染对胃癌细胞恶性表型的影响；利用TCGA数据库的及自行收集胃癌样本的基因表达谱深度测序，确定胃癌组织中特异表达的HCMV基因；在分析目标HCMV基因表达与胃癌临床病理特征相关性的基础上，评价HCMV基因对胃癌细胞生物学特性影响，结合胃癌动物模型体内实验，明确胃癌相关HCMV基因的生物学效应；最后，通过蛋白质组学结合免疫共沉淀等技术筛选、鉴定HCMV基因调控的关键蛋白，并评价其效应，阐明胃癌相关HCMV基因的效应机制。本项目首次阐明HCMV是胃癌组织中常见的病毒感染类型，其不同感染状态表达与胃癌患者预后存在相反的关联。HCMV增殖性感染促进胃癌的恶性表型，但有些HCMV潜伏相关基因表达可作为病毒源性抑癌基因，如UL138可通过与HSP70等分子相互作用，抑制胃癌细胞的增殖、促进细胞凋亡；UL135可通过影响F-actin细胞骨架，抑制胃癌细胞的转移。本项目的开展将从HCMV感染与胃癌关系这个全新的角度进一步探讨胃癌的发病机制，为胃癌防治提供新的靶点和策略。