HBV replication and carcinogenesis

描述(申请人提供)：乙肝病毒(乙肝病毒)是一种嗜肝病毒，可导致严重的肝脏疾病，包括急慢性肝炎、肝硬变和肝细胞癌(HCC)。世界上有3.5亿-4亿人慢性感染这种病毒，估计每年导致100万人死亡。在美国，慢性乙肝病毒携带者人口约为120万，在中国，携带者人口约为1亿。最近，我们发现，乙肝病毒可以诱导自噬来增强其DNA复制。我们还发现，在小鼠模型中，损害自噬可以诱导肝癌的发生，但会阻碍肝癌的进展。我们以前的这些研究证明了自噬在乙肝病毒复制和癌变中的重要作用。我们建议的研究将继续这些新的发现，以进一步研究乙肝病毒与其宿主之间的相互作用。具体地说，我们将研究乙肝病毒诱导自噬的分子机制。我们最近的研究表明，HBVX蛋白可以与III类磷脂酰肌醇-3-激酶(PI3KC3)结合，从而增强其酶活性。因此，我们将进一步确定HBx和PI3KC3之间的这种相互作用是如何诱导自噬的。我们还将研究自噬如何增强HBVDNA复制。我们将确定自噬空泡是否作为HBVDNA复制的平台，以及自噬是否影响调节HBVDNA复制的细胞因子。最后，我们将确定自噬在乙肝病毒诱导的肝癌发生中的作用。我们将研究为什么自噬受损促进了肝癌的发生，但同时又抑制了它的进展。我们的注意力将集中在没有和存在自噬的情况下产生的肝肿瘤的表型差异，肿瘤抑制因子在肝癌发生中的作用，以及自噬对肝肿瘤起始干细胞的影响。我们提出的研究将产生重要的信息，为我们了解乙肝病毒与其宿主细胞之间的相互作用，并导致更好地了解乙肝病毒的复制和致癌。

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases including acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). There are 350-400 million people in the world chronically infected by this virus, resulting in an estimated 1 million deaths every year. In the U.S., the chronic HBV carrier population is about 1.2 million and in China, the carrier population is about 100 million. Recently, we discovered that HBV could induce autophagy to enhance its DNA replication. We also found that impairing autophagy could induce the initiation but impede the progression of hepatocarcinogenesis in a mouse model. These previous studies of ours demonstrated an important role of autophagy in HBV replication and carcinogenesis. Our proposed research is to continue these novel findings to further study the interplay between HBV and its host. Specifically, we will study the molecular mechanism of HBV-induced autophagy. Our recent studies indicated that the HBV X protein could bind to the class III phosphatidylinositol-3-kinase (PI3KC3) to enhance its enzymatic activity. For that reason, we will further determine how this interaction between HBx and PI3KC3 induces autophagy. We will also investigate how autophagy enhances HBV DNA replication. We will determine whether autophagic vacuoles serve as the platform for HBV DNA replication and whether autophagy affects cellular factors that regulate HBV DNA replication. Finally, we will determine the role of autophagy in HBV-induced hepatocarcinogenesis. We will examine why impairing autophagy facilitates the initiation of hepatocarcinogenesis and yet in the mean time inhibits its progression. Our attention will be focused on the phenotypic difference of liver tumors produced in the absence and presence of autophagy, the role of tumor suppressors in hepatocarcinogenesis, and the effect of autophagy on hepatic tumor-initiating stem cells. Our proposed research will generate important information for us to understand the interaction between HBV and its host cell and lead to a better understanding of HBV replication and carcinogenesis.