HBV transgenic mice as a model for liver oncogenesis

描述：B型肝炎病毒（HBV）是肝细胞癌（HCC）的主要原因。然而，HBV如何导致HCC仍然存在争议。目前尚不清楚乙型肝炎病毒是否可以直接导致肝癌，还是仅通过诱导慢性肝脏炎症间接导致肝癌。由于乙型肝炎病毒的宿主范围较窄，且缺乏方便的动物模型，乙型肝炎病毒诱发肝细胞癌的研究一直比较困难。近年来，携带HBV全基因组的转基因小鼠已经被生产出来，并被用作研究HBV复制和发病机制的替代模型。这些小鼠很少发生肝细胞瘤形成。然而，在我们的初步研究中，发现这些小鼠如果暴露于致癌物二乙基亚硝胺（DEN），就会高频率地发生肝脏肿瘤。相比之下，在相同的实验条件下，对照幼稚小鼠以非常低的频率发生肝肿瘤。这些初步研究表明，HBV可以直接促进由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使用该动物模型进一步了解HBV诱导的肝细胞癌发生机制。有两个具体目标。第一个目的是研究HBV如何与DEN相互作用以诱导肝肿瘤，并确定可能参与此致癌过程的病毒和宿主因素。男性HBV携带者比女性HBV携带者更容易发展为HCC。雄激素及其受体被认为在这种性别差异中起重要作用。我们的初步研究表明，HBV X蛋白可以增强雄激素受体（AR）的基因反式激活活性。因此，本申请的第二个目的是研究HBV X蛋白是否可以增强AR介导的肝细胞癌发生。

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.