Liu J, Lian Z, Han S, Waye M M Y, Wang H, Wu M-C, Wu K, Ding J, Arbuthnot P, Kew M, Fan D, Feitelson M A
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA, and State Key Laboratory for Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Xi'an, Shaanxi, Peoples Republic of China.
Oncogene. 2006 Feb 16;25(7):1008-17. doi: 10.1038/sj.onc.1209138.
Hepatitis B virus (HBV)-encoded X antigen (HBxAg) contributes to the development of hepatocellular carcinoma (HCC). A frequent characteristic of HCC is reduced or absent expression of the cell adhesion protein, E-cadherin, although it is not known whether HBxAg plays a role. To address this, the levels of E-cadherin were determined in HBxAg-positive and -negative HepG2 cells in culture, and in tumor and surrounding nontumor liver from a panel of HBV carriers. The results showed an inverse relationship between HBxAg and E-cadherin expression both in tissue culture and in vivo. In HBxAg-positive cells, E-cadherin was suppressed at both the mRNA and protein levels. This was associated with hypermethylation of the E-cadherin promoter. Depressed E-cadherin correlated with HBxAg trans-activation function, as did the migration of HepG2 cells in vitro. Decreased expression of E-cadherin was also associated with the accumulation of beta-catenin in the cytoplasm and/or nuclei in tissues and cell lines, which is characteristic of activated beta-catenin. Additional work showed that HBxAg-activated beta-catenin. Together, these results suggest that the HBxAg is associated with decreased expression of E-cadherin, accumulation of beta-catenin in the cytoplasm and nucleus, and increased cell migration, which may contribute importantly to hepatocarcinogenesis.
乙型肝炎病毒（HBV）编码的X抗原（HBxAg）在肝细胞癌（HCC）的发生发展中起作用。HCC的一个常见特征是细胞黏附蛋白E-钙黏蛋白的表达降低或缺失，尽管尚不清楚HBxAg是否发挥作用。为了解决这个问题，我们检测了培养的HBxAg阳性和阴性HepG2细胞中，以及一组HBV携带者的肿瘤及周围非肿瘤肝脏组织中E-钙黏蛋白的水平。结果显示，在组织培养和体内实验中，HBxAg与E-钙黏蛋白的表达呈负相关。在HBxAg阳性细胞中，E-钙黏蛋白在mRNA和蛋白质水平均受到抑制。这与E-钙黏蛋白启动子的高甲基化有关。E-钙黏蛋白表达降低与HBxAg的反式激活功能相关，体外培养的HepG2细胞迁移也与之相关。E-钙黏蛋白表达降低还与组织和细胞系中β-连环蛋白在细胞质和/或细胞核中的积累有关，这是激活的β-连环蛋白的特征。进一步研究表明，HBxAg可激活β-连环蛋白。这些结果共同表明，HBxAg与E-钙黏蛋白表达降低、β-连环蛋白在细胞质和细胞核中的积累以及细胞迁移增加有关，这可能对肝癌发生起重要作用。
