Distinctive gene expression profiles associated with Hepatitis B virus x protein

Hepatitis B virus (HBV) is a major risk factor for the development of hepat ocellular carcinoma (HCC), HBV encodes the potentially oncogenic HBx protei n, which mainly functions as a transcriptional co-activator involving in mu ltiple gene deregulations. However, mechanisms underlying HBx-mediated onco genicity remain unclear, To determine the role(s) of HBx in the early genes is of HCC, we utilized the NCI Oncochip microarray that contains 2208 human cDNA clones to examine the gene expression profiles in either freshly isol ated normal primary adult human hepatocytes (Hhep) or an HCC cell line (SK- Hep-l) ecotopically expressing HBx via an adenoviral system. The gene expre ssion profiles also were determined in liver samples from HBV-infected chro nic active hepatitis patients when compared with normal liver samples. The microarray results were validated through Northern blot analysis of the exp ression of selected genes. Using reciprocally labeling hybridizations, scat terplot analysis of gene expression ratios in human primary hepatocytes exp ressing HBx demonstrates that microarrays are highly reproducible. The comp arison of gene expression profiles between HBx-expressing primary hepatocyt es and HBV-infected liver samples shows a consistent alteration of many cel lular genes including a subset of oncogenes (such as c-myc and c-myb) and t umor suppressor genes (such as APC, p53, WAF1 and WT1), Furthermore, cluste ring algorithm analysis showed distinctive gene expression profiles in Hhep and SK-Hep-l cells. Our findings are consistent with the hypothesis that t he deregulation of cellular genes by oncogenic HBx may be an early event th at favors hepatocyte proliferation during liver carcinogenesis.