New mouse model of hepatitis B virus-associated hepatocellular carcinoma

描述(申请人提供)：乙肝病毒(乙肝病毒)是严重肝病的主要原因，包括慢性肝炎，肝硬变和肝细胞癌(肝细胞癌)在世界各地和美国，特别是在少数族裔，如非裔美国人，亚裔美国人和印第安人。然而，慢性乙型肝炎致癌的分子机制尚不清楚。尽管慢性炎症和饮食致癌物等非特异性因素显然发挥了重要作用，但关于乙肝病毒特异性因素如何导致癌症，目前还没有确切的数据。最近的临床数据表明，肝癌和乙肝病毒突变与表面基因前S2区域的框内缺失和/或错义起始密码子突变有关。更重要的是，我们已经产生了含有前S2突变的乙肝病毒基因组的转基因小鼠，并表明它们会患上肝癌。因此，这些小鼠构成了一种新的和临床相关的乙肝诱导的肝细胞癌的动物模型。我们提出了两组实验。1)我们将跟踪观察这些小鼠在不同时间点的肝脏组织病理学，以便更详细地了解肝细胞癌形成的时间进程及其与前驱病变的关系。2)我们将对这些肝组织进行分子分析，以确定内质网应激和氧化应激是否可能在机制上参与癌症的发生。我们还将把小鼠的数据与我们将从人类肝脏样本中获得的数据联系起来。预计这些实验将验证这一独特的小鼠模型，并为了解乙肝病毒感染者致癌的分子基础奠定基础，从而为设计这种致命疾病的新预防和治疗措施指明未来的途径。乙肝病毒是世界上造成痛苦和死亡的主要原因，它会导致肝脏损伤、肝硬变(肝疤痕形成)和肝癌。它是仅次于人类免疫缺陷病毒的第二大人类病毒，每年导致120多万人死亡。目前的治疗是昂贵和不足的，我们相信我们的研究将导致开发新的方法来预防、检测或治疗这些患者的肝癌。

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a major cause of serious liver diseases, including chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) throughout the world and the US, especially among minorities such as African Americans, Asian Americans, and Native Americans. Yet, the molecular mechanisms of carcinogenesis in chronic hepatitis B remain unsettled. Although it is clear that non-specific factors such as chronic inflammation and dietary carcinogens play important roles, there are no firm data on how HBV-specific factors may contribute to carcinogenesis. Recent clinical data have pointed to an association between HCC and HBV mutants with in-frame deletions and/or missense start codon mutation in the preS2 region of the surface gene. More importantly, we have generated transgenic mice containing a preS2 mutant HBV genome and shown that they develop HCC. These mice therefore constitute a novel and clinically relevant animal model of HBV-induced HCC. We propose two sets of experiments. 1) We will follow a cohort of these mice and study the histopathology of their livers at various time points, so that we can obtain a detailed understanding of the time course of HCC formation and the relationship to precursor lesions. 2) We will perform a molecular analysis of these liver tissues, to determine if ER stress and oxidative stress may be mechanistically involved in carcinogenesis. We will also relate the murine data to data we will obtain from human liver specimens. It is anticipated that these experiments will validate this unique mouse model and provide the groundwork for understanding the molecular basis of carcinogenesis in HBV-infected people, thereby pointing to future ways for designing novel preventive and therapeutic measures for this deadly disease. Hepatitis B virus is a major cause of suffering and death in the world, by causing liver injury, cirrhosis (liver scarring) and liver cancer. It is the second most deadly human virus, after human immunodeficiency virus, and causes more than 1.2 million deaths annually. Current treatment is expensive and inadequate, and we believe that our research will lead to the development of new ways to prevent, detect, or treat liver cancer in these patients.