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FIGURE 17.1. Indirect and direct mechanisms and the integration of the HBV genome into cellular DNA.

occur through the interaction with cellular transcription factors in the nucleus, through posttranscriptional modulation of their activities or through affecting signal transduction cascades in the cytoplasm.26 HBV X binds p53,191 inhibiting p53-mediated transcriptional transactivation192 and apopto-sis.193 A close correlation has been observed between the HBV X-p53 interaction and the development of HCC in a transgenic mouse model.194 The mechanism of p53 inhibition by HBV X is unique, because p53 is sequestered by HBV X in the cytoplasm of hepatocytes,195 thereby blocking entry of p53 into the nuclear compartment. A further mechanism by which the HBV X protein could influence HCC development is through binding to components of DNA repair complexes. For example, the X protein binds to a human homologue of a UV light-damaged DNA-binding protein in monkeys.196 The X protein also blocks binding of p53 to a transcription factor, ERCC3, involved in DNA repair.192 The disruption of the fidelity of DNA repair, mediated by the X protein, may contribute to the genetic alterations observed in infected hepatocytes. HBV DNA integration in some HCCs can result in the deletion of the 3'-end of the HBV X and pre-S/S genes. This deletion leads to the synthesis of truncated pre-S/S pro teins, which exhibit transactivation potential for a wide range of cellular genes involved in cell proliferation such as PKC, c-raf, AP-1, and NF-kB.197

HBV may also elicit an indirect promoting effect in liver cancer. This effect is related to the immunopathogenesis of chronic HBV infection. The T-cell-mediated immune response to HBV antigens, mostly derived from HBcAg epi-topes located on the surface of hepatocytes, normally kills infected cells in the liver and clears the organ from HBV infection. When this cellular immune response is ineffective, the HBV infection progresses from acute to chronic hepatitis and, in some patients, to liver cirrhosis. During this process, the coexistent inflammation and hepatocyte regeneration increase the risk of HCC development. Liver cell proliferation in the presence of inflammation and of inflammatory mediators favors accumulation of genomic alterations, which can lead to hepatocyte transformation. During the inflammatory response, lymphocytes and macrophages produce cytokines and growth factor that stimulate hepatocyte proliferation. The phagocytic cells release products of the oxidative metabolism such as H2O2 and hydroxyl radicals.180,183 Oxygen free radicals, produced by activated Kupffer cells, lead to the formation of

8-hydroxyguanosine adducts, which are promutagenic DNA lesions inducing G to T transversion.180,183 The role of hepato-cyte necrosis and regeneration in hepatocarcinogenesis is best illustrated by Chisari's model of HbsAg transgenic mice.198,199 These mice overproduce the HBV large envelope polypeptide, accumulate toxic quantities of HBsAg within the hepatocytes, and develop a severe, prolonged hepatocellular injury. This lesion triggers inflammation, regenerative hyperplasia, tran-scriptional deregulation, and aneuploidy, finally progressing to neoplasia. These results are supported by the evidence that mice transgenic for the TGF-a gene, showing continuous mitogenic stimulation of hepatocytes, develop liver cancer.200 In human chronic hepatitis, liver injury may be due to either the immune response during HBV infection or the toxic effects of alcohol.30,181,201 In summary, severe prolonged cellular injury and persistent growth stimulation induce a proliferative response, which leads to genetic damage that can lead to tumor development. It should be noted that HBV also replicates in extrahepatic sites, such as bone marrow, lymphoid cells, pancreas, and kidneys.202,203 Therefore, clearance of the virus from hepatocytes may not cure the disease, and HBV moving from these extrahepatic locations may reinfect the liver after transplant.202

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