A cellular gene up-regulated by hepatitis B virus-encoded X antigen promotes hepatocellular growth and survival

Polymerase chain reaction (PCR) select complementary DNA. (cDNA) subtractio n of hepatitis B x antigen (HBxAg)-positive compared with -negative HepG2 c ells resulted in the up-regulated expression of a cellular gene that encode s a transcript of 745 bases and a polypeptide 99 amino acids long. GenBank analysis revealed extensive homology with the amino terminal domain of cell ular multidrug resistant proteins (MRP), although overexpression of this ge ne did not confer an MRP phenotype. In situ hybridization and immunostainin g showed colocalized expression with HBxAg in the liver of hepatitis B carr iers. Overexpression of this protein stimulated the growth of HepG2 cells i n serum-free medium, and partially protected cells from anti-Fas-mediated k illing, but did not promote growth in soft agar or tumor formation in nude mice. Introduction of the dominant negative inhibitor of nuclear factor kap paB (I kappaB alpha) into HBxAg-positive HepG2 cells decreased the levels o f messenger RNA (mRNA) and protein, suggesting that its up-regulation is nu clear factor kappaB (NF-kappaB) dependent. Hence, HBxAg activation of NF-ka ppaB may result in the up-regulation of a cellular protein that promotes gr owth factor-independent survival and protects against Fas-mediated killing. This factor may contribute to the persistence of infected hepatocytes duri ng chronic infection, which is important for the later development of hepat ocellular carcinoma (HCC).