Hepatitis B Virus (HBV) is a major causative agent of hepatocellular carcinoma (HCC) but the pathogenesis remains Poorly understood. To provide novel insights into the pathogenesis of HBV, we examined the expression profile of HBV-positive HepG2.2.15 and -negative HepG2 cells. Genes that were markedly up- or down-regulated in the presence of HBV are involved in signal transduction, apoptosis, transcriptional regulation, protein degradation and oncogenesis. Among the analyzed co-signaling molecules CD40, CD80, CD86, 137-H1, B7-DC, OX40, and B7RP-1, CD40 was the only one up-regulated. Following establishment of stable HepG2 cell lines transfected with HBV genes, we found that HBxAg Up-regulated the expression of CD40. We also found that CD40 activation by CD40L could promote the expression of negative co-signaling molecule B7-H1, rather than induce the apoptosis of HepG2HBx cell as expected. These results suggest that CD40 up-regulation by HBxAg may play a facilitating role in the pathogenesis causing HCC. (c) 2009 Published by Elsevier Inc.