HBV transgenic mice as a model for liver oncogenesis

HBV转基因小鼠作为肝癌发生的模型

• 批准号: 7296109
• 负责人: J.-H. James Ou
• 金额: $ 23.74万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-17 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7296109
• 关键词: Androgen Receptor; Androgens; Animal Model; Binding; Carcinogens; Cells; Chronic; Condition; Diethylnitrosamine; Exposure to; Female; Frequencies; Genes; Genome; Goals; Hepatitis B Virus; Hepatitis B X-Protein; Hepatocarcinogenesis; Inflammation; Injury; Integration Host Factors; Liver; Liver neoplasms; Mediating; Modeling; Molecular; Mus; Neoplasms; Oncogenic; Pathogenesis; Pathway interactions; Play; Primary carcinoma of the liver cells; Process; Proteins; Purpose; Range; Research; Risk Factors; Role; Sex Characteristics; Study models; Testing; Thinking; Transactivation; Transgenic Mice; Viral; Virus; Virus Replication; male; mouse model; novel; receptor; tumorigenesis

DESCRIPTION: Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). However, how HBV may cause HCC remains controversial. It is unclear whether HBV can directly cause HCC or only indirectly cause HCC via the induction of chronic liver inflammation. The research on hepatocellular carcinogenesis induced by HBV has been difficult due to the narrow host range of this virus and the lack of a convenient animal model for its research. In recent years, transgenic mice carrying the entire HBV genome have been produced and used as a surrogate model for studying HBV replication and pathogenesis. These mice rarely develop hepatocellular neoplasia. However, in our preliminary studies, these mice were found to develop liver tumors at high frequencies if they were exposed once to the carcinogen diethylnitrosamine (DEN). In contrast, the control naive mice developed liver tumors at a very low frequency under the same experimental conditions. These preliminary studies indicate that HBV can directly promote hepatocellular oncogenesis initiated by carcinogens. The goal of this exploratory research application is to use this animal model to further understand the mechanisms of HBV-induced hepatocellular carcinogenesis. There are two specific aims. The first aim is to study how HBV interacts with DEN to induce liver tumors and to identify viral and host factors that may be involved in this oncogenic process. Male HBV carriers are more likely to develop HCC than female HBV carriers. Androgen and its receptor are believed to play an important role in this gender difference. Our preliminary studies indicate that the HBV X protein can enhance the gene transactivation activity of the androgen receptor (AR). Thus, the second aim of this application is to investigate whether the HBV X protein can enhance hepatocellular carcinogenesis mediated by AR.

描述：乙肝病毒是导致肝细胞癌的主要原因。然而，乙肝病毒如何导致肝细胞癌仍存在争议。目前尚不清楚乙肝病毒是否可直接导致肝细胞癌，还是仅通过诱导慢性肝脏炎症间接导致肝细胞癌。由于该病毒宿主范围狭窄，缺乏简便的动物模型，导致其诱发肝细胞癌变的研究一直比较困难。近年来，携带乙肝病毒全基因组的转基因小鼠已被培育出来，并被用作研究乙肝病毒复制和发病机制的替代模型。这些小鼠很少发生肝细胞肿瘤。然而，在我们的初步研究中，发现这些小鼠如果接触致癌物质二乙基亚硝胺(DEN)一次，就会出现高频率的肝肿瘤。相比之下，在相同的实验条件下，对照组幼鼠发生肝脏肿瘤的频率非常低。这些初步研究表明，乙肝病毒可以直接促进致癌物引发的肝细胞癌的发生。本探索性研究应用的目的是利用这一动物模型进一步了解乙肝病毒诱导的肝细胞癌的发生机制。有两个具体目标。第一个目的是研究乙肝病毒如何与DEN相互作用诱发肝脏肿瘤，并确定可能参与这一致癌过程的病毒和宿主因素。男性乙肝病毒携带者比女性乙肝病毒携带者更容易患上肝癌。雄激素及其受体被认为在这种性别差异中起着重要作用。我们的初步研究表明，HBVX蛋白可以增强雄激素受体(AR)的基因反式激活活性。因此，这项应用的第二个目的是研究HBVX蛋白是否能促进AR介导的肝细胞癌的发生。