THE ROLE OF HEPATITIS-B VIRUS (HBV) IN THE DEVELOPMENT OF HEPATOCELLULAR-CARCINOMA

Based on epidemiological data and experimental results, mammalian hepa dnaviruses, in particular hepatitis B virus (HBV) and woodchuck hepati tis virus (WHV), have to be considered as a causative factor in the de velopment of hepatocellular carcinoma (HCC), despite the fact that the y lack a complete viral oncogene. Integrated viral DNA is found regula rly in woodchuck and human HCC. In woodchucks an activation in cis of c-myc and N-myc is almost always observed By contrast, in humans, a pl eiotropic activation in trans of cellular genes by integrated genes en coding HBV transactivators, namely the X protein (HBx) and the PreS2 a ctivators (the large surface protein (LHBs) and truncated middle surfa ce proteins (MHBst)), has been described as a general mechanism. Mimic king chemical tumour promoters, i.e. TPA, the viral transactivators tr igger PKC/Raf-controlled signalling pathways, finally activating trans cription factors such as AP-1 and NF-kappa B which control genes relev ant for proliferation. Moreover, 'HBV-transactivated' hepatocytes may give rise to a new epigenetic situation in the form of an 'immortalize d' inflammatory process which may then pave the way for further critic al events such as mutations and chromosomal aberrations.