Synergy between transforming growth factor alpha and hepatitis B virus surface antigen in hepatocellular proliferation and carcinogenesis.
Synergy between transforming growth factor alpha and hepatitis B virus surface antigen in hepatocellular proliferation and carcinogenesis.
复制标题
转化生长因子α和乙型肝炎病毒表面抗原在肝细胞增殖和癌变中的协同作用。
作者：
John Jakubczak;F. Chisari;Glenn Merlino
慢性感染B型肝炎病毒（HBV）可导致人类肝癌。表达HBV主要包膜蛋白HBV表面抗原（HBsAg）的转基因小鼠代表了人类感染的一些组织病理学效应的实验模型，包括肝细胞损伤、坏死、增生延长和肝肿瘤发生率升高。对慢性肝损伤的再生性增生反应被认为是癌症风险增加的关键因素。然而，很少有人知道介导再生增殖的细胞因子。一个候选者是肝细胞有丝分裂原转化生长因子α（TGF-α）;在HBV感染的肝癌患者中，TGF-α和HBsAg在同一肝细胞中积累。过表达TGF-α的转基因小鼠表现出增强的肝细胞增殖率并发展为肝细胞癌。在这项研究中，我们已经分析了TGF-α和HBsAg在肝脏中的共表达的影响，使用双转基因小鼠模型。我们发现，肝细胞携带TGF-α和HBsAg转基因表现出增长相对于肝细胞与任何单独的转基因。此外，与单转基因TGF-α或HBsAg同窝仔相比，双转基因雄性（而非雌性）出现肝细胞癌的速度显著加快。这些结果表明，HBsAg和TGF-α在肝脏中的协同活性，可能是通过首先刺激静止的肝细胞进入G1期，随后促进其通过细胞周期的运输，分别。此外，我们的数据支持的论点，TGF-α参与HBV感染患者诱导的肝癌发生。
Chronic infection with hepatitis B virus (HBV) can cause liver cancer in humans. Transgenic mice expressing the major envelope protein of HBV, HBV surface antigen (HBsAg), represent an experimental model for some of the histopathological effects of infection in humans, including prolonged hepatocellular injury, necrosis, hyperplasia, and an elevated incidence of liver tumors. The regenerative hyperplastic response to the chronic liver damage is thought to be a critical factor in the increased risk of cancer. However, little is known about the cellular factors that mediate regenerative proliferation. One candidate is the hepatocyte mitogen transforming growth factor alpha (TGF-alpha); in HBV-infected patients with liver cancer, TGF-alpha and HBsAg accumulate in the same hepatocytes. Transgenic mice overexpressing TGF-alpha demonstrate enhanced hepatocyte proliferation rates and develop hepatocellular carcinomas. In this study, we have analyzed the effect of TGF-alpha and HBsAg coexpression in the liver using a bitransgenic mouse model. We show that hepatocytes harboring both the TGF-alpha and HBsAg transgenes exhibited an increase in growth relative to hepatocytes with either transgene alone. Furthermore, bitransgenic males but not females had a dramatically accelerated appearance of hepatocellular carcinomas, compared to single transgenic TGF-alpha or HBsAg littermates. These results demonstrate synergistic activity between HBsAg and TGF-alpha in the liver, probably by first stimulating quiescent hepatocytes to enter G1 and by subsequently promoting their transit through the cell cycle, respectively. Moreover, our data support the contention that TGF-alpha participates in HBV-induced hepatocarcinogenesis in infected patients.