Feitelson Mark A, Reis Helena M G P V, Tufan N Lale, Sun Bill, Pan Jingbo, Lian Zhaorui
Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
Cancer Lett. 2009 Dec 1;286(1):69-79. doi: 10.1016/j.canlet.2008.12.010. Epub 2009 Feb 6.
Under most circumstances, hepatitis B virus (HBV) is noncytopathic. However, hepatocellular regeneration that accompanies each bout of hepatitis appears to be associated with increased integration of HBV DNA fragments expressing the virus encoded hepatitis B x antigen (HBxAg). Intrahepatic HBxAg staining correlates with the intensity and progression of chronic liver disease (CLD), and additional work has shown that HBxAg blocks immune mediated killing by Fas and by tumor necrosis factor alpha (TNFalpha). This is not only associated with the blockage of caspase activities by HBxAg, but also by the constitutive stimulation of hepatoprotective pathways, such as nuclear factor kappa B (NF-kappaB), phosphoinositol 3-kinase (PI3K), and beta-catenin (beta-catenin). HBxAg also appears to promote fibrogenesis, by stimulating the production of fibronectin. HBxAg also stimulates the production and activity of transforming growth factor beta1 (TGFbeta1) by several mechanisms, thereby promoting the profibrogenic and tumorigenic properties of this important cytokine. In addition, HBxAg appears to remodel the extracellular matrix (ECM) by altering the expression of several matrix metalloproteinases (MMPs), which may promote tumor metastasis. Hence, HBxAg appears to promote chronic infection by preventing immune mediated apoptosis of infected hepatocytes, by promoting the establishment and persistence of fibrosis and cirrhosis preceding the development of HCC, and by promoting the remodeling of EMC during tumor progression.
在大多数情况下，乙型肝炎病毒（HBV）无细胞病变作用。然而，每次肝炎发作伴随的肝细胞再生似乎与表达病毒编码的乙型肝炎x抗原（HBxAg）的HBV DNA片段整合增加有关。肝内HBxAg染色与慢性肝病（CLD）的严重程度和进展相关，进一步研究表明，HBxAg可阻断Fas和肿瘤坏死因子α（TNFα）介导的免疫杀伤作用。这不仅与HBxAg阻断半胱天冬酶活性有关，还与肝保护途径如核因子κB（NF-κB）、磷酸肌醇3激酶（PI3K）和β-连环蛋白（β-catenin）的持续激活有关。HBxAg似乎还通过刺激纤连蛋白的产生促进纤维生成。HBxAg还通过多种机制刺激转化生长因子β1（TGFβ1）的产生和活性，从而增强这种重要细胞因子的促纤维化和致瘤特性。此外，HBxAg似乎通过改变几种基质金属蛋白酶（MMP）的表达来重塑细胞外基质（ECM），这可能促进肿瘤转移。因此，HBxAg似乎通过阻止免疫介导的受感染肝细胞凋亡、促进HCC发生之前纤维化和肝硬化的形成与持续存在以及促进肿瘤进展过程中EMC的重塑来促进慢性感染。
