The role of hepatitis B virus (HBV) in the development of hepatocellular carcinoma Eberhard Hildt, Peter Hans Hofschneider and Stephan Urban Based on epidemiological data and experimental results, mammalian hepadnaviruses, in particular hepatitis B virus (HBV) and woodchuck hepatitis virus (WHV), have to be considered as a causative factor in the development of hepatocellular carcinoma (HCC), despite the fact that they lack a complete viral oncogene. Integrated viral DNA is found regularly 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 pleiotropic activation in trans of cellu lar gen es by in tegrated genes encoding HBV transactivators, namely the X protein (HBx) and the PreS2 activators (the large surface protein (LHBs) and truncated middle surface proteins (MHBs t )), has been described as a general mechanism. Mimicking chemical tumour promoters, i.e. TPA, the viral transactivators trigger PKC/ Raf-controlled signalling pathways, finally activating transcription factors such as AP-1 and NF- κB which con trol gen es relevant for proliferation. Moreover, ‘HBV-transactivated’ hepatocytes may give rise to a new epigenetic situation in the form of an ‘immortalized’ inflammatory process which may then pave the way for further critical events such as mutations and chromosomal aberrations. Key words: hepadnaviruses / oncogenesis / viral transactivators / PKC/ Raf-controlled signalling pathways ©1996 Academic Press Ltd V IRUS- ASSOCIATED TUMOURS comprise approximately 15% of all tumours in humans worldwide. 1 Assu m in g the implicated viruses play a causative role in oncoge- nesis, then viruses are among the most important oncogenic agents worldwide. Among the virus-asso- ciated tumours, approximately 30% are HBV-asso- ciated hepatocellular carcinomas, which means 4.5% of all tumours worldwide. From an epidemiological viewpoint, the risk for males with chronic HBV infection, i.e. HBsAg carriers and those with chronic persistent and chronic aggres- sive hepatitis, of developing HCC increases by a factor of ~ 100. 2,3 For chronically infected males living in Taiwan this means a lifetime risk of dying of HCC of almost 50%. Apart from a few exceptions (Greece, for example) the geographical correlation between HBsAg prevalence and the incidence of HCC is very high. At present more than 200 million people worldwide are chronically infected; every year two million die as a result of the infection, approximately 700,000 of whom die of HBV-associated HCC (reviewed in ref 4). Although an HBV vaccine exists, the WHO estimates that 400 million people will be chronically infected by the year 2000. Since the incubation period for the development of HBV- associated HCC is as long as 30 years or more, this means that this tumour will remain a major public health problem for decades, if better therapies cannot be found to supplement those now in existence. At present, as curative therapies, only liver resection, orthotopic liver transplantation and, in Asia, ethanol injection into the tumour are available. This situation alone is serious enough to warrant further intensive studies into the causal relationship between HBV infection and the development of HCC. Intensive studies were started very soon after the cloning of HBV DNA in the late 1970s, which until then had been difficult to obtain. In addition, animal model systems were developed, and here in particular the woodchuck hepatitis virus (WHV) is worth men- tioning. As is well known, in newborn American woodchucks WHV induces the development of HCCs with a frequency of almost 100% within two to three years. As pointed out in a review by Rogler and Chisari, 5 many new facts have been discovered but no unifying concepts could be established: in tumours from infected woodchucks activation in cis of two cellular proto-oncogenes, namely c-myc and N-myc, by the insertion of WHV DNA into these genes or their flanking regions, including the so-called WIN locus, is almost always observed (reviewed in refs 5,6, and M. Buendia, personal communication). In HBV-positive human as in woodchuck HCCs, viral DNA is almost From the Abteilung Virusforschung, Max-Planck-Institut f¨ ur Biochemie, 82152 Martinsried, Germany seminars in VIROLOGY, Vol 7, 1996: pp 333–347 ©1996 Academic Press Ltd 1044-5773/96/050333 + 15 $25.00/0 333