The expression of LEF-1 was found closely NVP-HSP990 in vitro associated with the HBsAg expression in HBsAg positive HCC tissues. However no significant differences were observed either in LEF-1 protein or LEF-1 isoforms when compared between tumor cells and peritumor cells in these HBsAg negative tissues. The different expression patterns of LEF-1 between HBsAg positive and negative HCC tissues suggested that HBsAg could play important

roles in regulating Wnt signaling pathway, thus providing new insights into the involvement of HBsAg in hepatocarcinogenesis. However, the molecular mechanisms of HBsAg-LEF-1 interaction and their roles in the development of HCC merit further investigation. Other viral or cellular factors might also be involved in the interaction between HBV and Wnt pathway. For instance,

HBx has been reported to be essential for the activation of Wnt/b-catenin signalling in hepatoma cells [33], and reduced the phosphorylation level of b-catenin by suppressing GSK-3b function through the Erk pathway Thiazovivin cost [34]. Cyclin D1 and c-myc are key regulatory genes in the control of cell cycle and cell proliferation, and thus are the best-known candidates among the LEF-1 regulated genes [35, 36]. Over-expression of cyclin D1 ranged from 5.6% to 54% of HCCs and was associated with advanced clinicopathological stage [30]. Up-regulation of c-myc gene was reported by Kawate et al in 33% of HCCs by differential PCR analysis [37]. However, to date, the roles of cyclin D1 and c-myc in HCCs are still not well defined. In this study, expression of cyclin D1 and c-myc was markedly increased in HCC tissues, compared 6-phosphogluconolactonase with normal liver tissues

but the expression levels of these two genes were higher in peritumor cells than that of tumor cells. This could partly be attributed to the over-expression of 38 kDa dominant negative LEF-1 isoform in tumor cells. Up-regulation of 38 kDa dominant negative isoform of LEF-1 in tumor cells could suppress rather than activate the Wnt pathway. Therefore the downstream target genes, cyclin D1 and c-myc, were induced at a lower level in the tumor cells, compared to that of peritumor cells. However the complexity of cyclin D1 and c-myc in HBV-associated HCC tissues should be considered. Conclusion Taken together, as there was higher expression of HBsAg in peritumor cells and higher up-regulation of LEF-1 in the cytoplasm of cells, as well as higher up-regulation of cyclin D1 and c-my, it is predicted that HBsAg exerted pronounced effects on LEF-1 and its downstream genes in hepatocytes, resulting in more active cell proliferation, which could promote or enhance malignant transformation of hepatocytes by other viral or cellular mechanisms. It is postulated that HBsAg interacted with liver cells only at the pre-malignant stage, and thus plays the role of an initiator during the process of HCC development.