Chisari F V, Klopchin K, Moriyama T, Pasquinelli C, Dunsford H A, Sell S, Pinkert C A, Brinster R L, Palmiter R D
Department of Molecular and Experimental Medicine, Research Institute of Scripps Clinic, La Jolla, California 92037.
Cell. 1989 Dec 22;59(6):1145-56. doi: 10.1016/0092-8674(89)90770-8.
Transgenic mice that overproduce the hepatitis B virus large envelope polypeptide and accumulate toxic quantities of hepatitis B surface antigen (HBsAg) within the hepatocyte develop severe, prolonged hepatocellular injury that initiates a programmed response within the liver, characterized by inflammation, regenerative hyperplasia, transcriptional deregulation, and aneuploidy. This response inexorably progresses to neoplasia. The incidence of hepatocellular carcinoma in this model corresponds to the frequency, severity, and age of onset of liver cell injury, which itself corresponds to the intrahepatic concentration of HBsAg and is influenced by genetic background and sex. Thus, the inappropriate expression of a single structural viral gene is sufficient to cause malignant transformation in this model. These results suggest that severe, prolonged cellular injury induces a preneoplastic proliferative response that fosters secondary genetic events that program the cell for unrestrained growth.
过度产生乙肝病毒大包膜多肽并在肝细胞内积累大量有毒乙肝表面抗原（HBsAg）的转基因小鼠，会发生严重且持续时间长的肝细胞损伤，从而引发肝脏内的程序性反应，其特征为炎症、再生性增生、转录失调和非整倍体。这种反应不可避免地会发展为肿瘤形成。该模型中肝细胞癌的发生率与肝细胞损伤的频率、严重程度和发病年龄相对应，而肝细胞损伤本身又与肝内HBsAg浓度相对应，并受遗传背景和性别的影响。因此，在该模型中单个病毒结构基因的不适当表达足以导致恶性转化。这些结果表明，严重且持续时间长的细胞损伤会诱导肿瘤前增殖反应，促进继发性遗传事件的发生，从而使细胞具备不受限制生长的特性。
