key: cord-014920-mmykzj9w
authors: Wang, Shi-qun; Wu, Jian-guo
title: Biological effects of HBV X protein on hepatocellular carcinogenesis in association with cellular factors
date: 2008-05-10
journal: Virol Sin
DOI: 10.1007/s12250-008-2952-9
sha: 
doc_id: 14920
cord_uid: mmykzj9w

The X protein (HBx) of Human hepatitis B virus (HBV) acts as an indirect transcriptional transactivator to regulate the expression of many viral and cellular genes, as well as playing a critical role in pathogenesis and the development of Hepatocellular carcinoma (HCC). Here we described the biological effects of HBx in association with four cellular factors, including inflammatory factors (COX-2 and iNOS), oncoprotein (Ras), and a newly identified tumor suppressor (YueF). The characteristics of these effectors, which might be associated with hepatocellular carcinoma, are also discussed.

The genome of hepatitis B virus (HBV) is approximately 3 000 to 3 300 nucleotides in length, and molecular studies have suggested the presence of at least four genes in the viral genome: the S gene coding for the glycosylated envelope protein, C gene for the core protein, P gene for the HBV polymerase, and X gene for the X protein that is associated with transactivating properties (19) . HBV infection causes liver diseases that vary greatly in severity from person There is accumulating evidence suggesting a close association between chronic HBV infection and an increased risk for the development of primary hepatocellular carcinoma (HCC). Persistent infection by HBV results in sustained low level liver damage of infected hepatocytes. Almost all such damage can be attributed to attack by the host's immune system. The rate of hepatocyte proliferation must increase in order to compensate for cell loss. It is generally accepted that such an increased rate of proliferation over long periods is a major contributor to the development of liver cancer (7, 23, 25) . In addition, the inflammation and phagocytosis that are integral to the immune response can lead to increased local concentrations of Received: 2008-02-12, Accepted: 2008-03-02 superoxides and free radicals that are highly carcinogenic (1).

In addition, the viral X region appears to have pleiotropic effects that could also be involved in the oncogenic processes, including transcriptional activation of cellular growth regulatory genes, modulation of apoptosis and inhibition of nucleotide excision repair of damaged cellular DNA (8, 14, 16) . The effects of HBx are mediated by interaction with cell proteins and activation of cell signaling pathways.

Here we focus on the roles of four representative cellular factors (COX-2, iNOS, Ras, and YueF) that are associated with HBx and discuss their contributions to hepatitis B virus-associated hepatocarcinogenesis according mainly to our recent work.

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the pathway of prostaglandin (PG) synthesis, is one of the important cellular factors that have been suggested previously to be associated with inflammation caused by microbes infections (5, 15, 18) . Our Tumor suppressors are a specific group of proteins that appear to prevent formation of cancer and loss-offunction mutations in related genes enhance susceptibility to cancer. In a previous study, we used HBV X protein as a bait protein for screening a human liver cDNA library using a yeast two-hybrid system (27) . Many human hepatocellular carcinomas contain integrated HBV, and the viral X protein appears to have pleiotropic effects that could be involved in the oncogenic process. Through interaction with cell proteins, HBx also alter mechanisms of apoptosis and interfere with nucleotide excision repair of damaged DNA. Together with an influence on cellular signaling, these mechanisms may favor the cell's malignant clonal expansion. But we cannot forget that tumor formation in mammals is a much more complex process and we must make the best endeavors to make more apparent the role of viruses in the development of human cancer.

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