snoRNA生物发生在HBx促进肝癌发生发展中的作用研究

乙型肝炎病毒X蛋白（HBx）在慢性乙肝病理过程，和诱发肝癌的发生、发展到侵袭转移中，都发挥重要作用。生物甲基供体S-腺苷蛋氨酸(SAM)在维持肝细胞分化状态中起中心事件作用。我们既往发现HBx通过降低稳态SAM浓度引起肝癌细胞基因组异常甲基化而促进肝癌发展。在此基础上，发现HBx可以诱发多个小核仁RNA（snoRNA)及小核仁RNA结合蛋白表达失调；其中小核仁RNA宿主基因（SNHG6）与细胞稳态SAM产生存在关联。我们推测HBx诱发snoRNA生物发生失调通过不同的snoRNA通路多途径促进肝癌的发生发展，其中一条途径是通过SNHG6参与对肝癌细胞基因组异常甲基化的调控。本课题将从表观遗传学角度研究HBx与snoRNA通路的关系在肝癌发展中所起的作用，并用RNA-蛋白质互作分析研究SNHG6对细胞稳态SAM的调控机制。这将丰富我们对乙肝病毒致癌机制的认识，为肝癌的靶向治疗提供理论依据。

Hepatitis B virus X protein plays an important role in the pathological process of chronic hepatitis B, as well as the development, carcinogenesis and.metastasis of hepatocellular carcinoma (HCC), but the molecular mechanism remains unclear. S-Adenosylmethionine (SAM), derived from methionine catabolism in all mammalian cells, is not only the principal methyl donor, but also a crucial event in the maintenance of hepatocytes differentiation status. Our previously studies showed that HBx could cause genome-wide aberrant DNA methylation by reducing the production of the steady-state SAM in HCC, which contribute to hepatocarcinogenesis and development. Furthermore, we found that HBx could induce snoRNAs dysregulation and overexpression of fibrillarin (Fbl) HCC. And also, the host gene of small nucleolar RNA (SNHG6) reduces the production of steady-state SAM. We hypothesized that HBx could induce the disorders of snoRNA biogenesis, which may responsible for the occurrence and development of hepatocellular carcinoma HCC through different snoRNA pathways. One of snoRNA, SNHG6 could promote genome-wide aberrant DNA methylation through inhibiting the production of the steady-state SAM. This study will investigated the potential relationship between snoRNA pathway and HBx expression in the hepatocarcinogenesis and development from the point of epigenetic view, and then we will analyze the effect mechanism of SNHG6 on the steady-state SAM level in HCC. These studies will enrich our understanding of the molecular mechanism of the carcinogenic effect of hepatitis B virus, and provide a theoretical basis for the molecular target therapy for HCC.