Molecular Pathogenesis of Hepatitis-B-virus-associated Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent and malignant diseases worldwide. Epidemiological studies have clearly demonstrated that chronic hepatitis B virus (HBV) infection is a major etiological factor in the development of HCC. The pathogenesis of HBV-associated HCC has been studied extensively, and the molecular changes associated with malignant transformation have been identified. The predominant carcinogenic mechanisms of HBV-associated HCC are chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation. An important role is also played by the integration of HBV DNA into host cellular DNA, which disrupts or promotes the expression of cellular genes that are important in cell growth and differentiation. Especially, HBx protein is a transactivating protein that promotes cell growth, survival, and the development of HCC. Continued investigation of the mechanisms underlying hepatocarcinogenesis will refine our current understanding of the molecular and cellular basis for neoplastic transformation in the liver. Prevention of HBV infections and effective treatments for chronic hepatitis B are still needed for the global control of HBV-associated HCC. This review summarizes the current knowledge on the mechanisms involved in HBV-associated hepatocarcinogenesis. (Gut and Liver 2007;1: 101-117)

Ligand activation of peroxisome proliferator-activated receptor-β/δ suppresses liver tumorigenesis in hepatitis B transgenic mice

“…Approximately 600,000 humans die every year due to liver cancer that develops from hepatitis B virus (HBV) infection (Franco et al 2012). Chronic HBV infection induces persistent hepatocyte inflammation, oxidative DNA damage, uncontrolled cellular proliferation, fibrosis and cirrhosis, which eventually culminates in hepatocellular carcinoma (Park et al 2007). Since steatosis and inflammation are two important mechanisms that mediate HBV-dependent hepatocellular carcinoma, and ligand activation of PPARβ/δ prevents hepatic steatosis and inflammation, the present study examined the hypothesis that ligand activation of PPARβ/δ inhibits liver cancer in HBV transgenic mice.…”

Characterization of metastatic tumor antigen 1 and its interaction with hepatitis B virus X protein in NF-κB signaling and tumor progression in a woodchuck hepatocellular carcinoma model

“…The frequency of MTA1 overexpression is much higher in HBV-associated HCC (HBV–HCC) than in HCV-associated HCC [11]; however, the mechanisms underlying this observation remain elusive. The direct effects of HBV and indirect effects of inflammation, regeneration, and cirrhosis contribute to the development of HBV–HCC [15, 16]. Few studies have reported the potential role of MTA1 in HBV-associated hepatocarcinogenesis [17–19].…”

High HBV-DNA Titer in Surrounding Liver Rather Than in Hepatocellular Carcinoma Tissue Predisposes to Recurrence After Curative Surgical Resection

“…After inflammation, consistent necrosis of hepatocytes accompanied by rapid regeneration may lead to the accumulation of mutations and the selection of cells with malignant phenotypes. 20,21 That is, persistent inflammation in the remaining liver provides "field-effects" to develop second primary HCCs after hepatectomy. Intrahepatic HBV-DNA, especially at high titer, may also cause active inflammation in the remaining liver parenchyma, contributing to a change in tumor microenvironment, increasing HCC recurrence after hepatectomy.…”

“…[22][23][24][25] Alternatively, HBV itself may activate oncogenic signaling pathways, either cis-activation through integration of viral genetic material into host cellular DNA or trans-activation by viral products such as HBx protein. 21 FIGURE 1. Cumulative tumor recurrence in relation to intrahepatic hepatitis B virus (HBV)-DNA titers in nontumor liver tissue surrounding hepatocellular carcinomas.…”