Molecular viral oncology of hepatocellular carcinoma Timothy M Block* ,1 , Anand S Mehta 1 , Claus J Fimmel 1,2 and Robert Jordan 1 1 Department of Molecular Pharmacology and Biochemistry, Jefferson Center for Biomedical Research of Thomas Jefferson University, 700 East Butler Ave., Doylestown, PA 18901, USA; 2 Department of Internal Medicine, Division of Gastroenterology and Hepatology, St Louis University School of Medicine, St Louis, MO 63106, USA Hepatocellular carcinoma (HCC) is the fifth most common cancer, but the third leading cause of cancer death, in the world, with more than 500000 fatalities annually. The major etiology of HCC/liver cancer in people is hepatitis B virus (HBV), followed by hepatitis C virus infection (HCV), although nonviral causes also play a role in a minority of cases. Recent molecular studies confirm what was suspected: that HCC tissue from different individuals have many phenotypic differences. However, there are clearly features that unify HCC occurring in a background of viral hepatitis B and C. HCC due to HBV and HCV may be an indirect result of enhanced hepatocyte turnover that occurs in an effort to replace infected cells that have been immunologically attacked. Viral functions may also play a more direct role in mediating oncogenesis. This review considers the molecular and cellular mechanisms involved in primary hepatocellular carcinoma, using a viral perspective. Oncogene (2003) 22, 5093–5107. doi:10.1038/sj.onc.1206557 Keywords: hepatocellular carcinoma; liver cancer; he- patitis B; hepatitis C Introduction The majority of cases of hepatocellular carcinoma (HCC) in the world are due to hepatitis B virus (HBV), with the number of hepatitis C virus (HCV)-associated cases growing in the Western world (Figure 1) and the incidence of nonviral HCC is also rising in the US (El-Serag and Mason, 1999; Parkin et al., 2001). As shown in Figure 2, HCC is the fifth most frequent cancer in the world, with an estimate of more than 500000 incidences in 2000. Primary hepatocellular carcinoma (PHCC) refers to HCC originat- ing within the liver. Although some of the information discussed in this review is based upon studies that do not definitively identify the HCC as primary, since most of the HCC discussed here is associated with HBV and HCV and is PHCC, HCC and PHCC designations will be used interchangeably. Despite being fifth in cancer incidence, worldwide, HCC is the third leading cause of cancer death (Figure 3). The high mortality associated with HCC is because it is often unresponsive to treatment. The high mortality may be in part because the noncapsular part of the liver is lacking in sensory fibers and symptoms of HCC often occur late PHCC and with a 5-year survival rate of less than 5% with or without therapeutic intervention (El-Serag et al., 1999). Moreover, the number of deaths due to PHCC is expected to rise over the next 20 years. Those chronically infected with HBV have a life risk of death to PHCC of between 10 and 25% (Evans et al., 1998; El-Serag et al., 1999; Montalto et al., 2002). The epidemiology and natural history of HCV is somewhat less understood, but it appears that the lifetime risk of HCC in those chronically infected with HCV will be between 2 and 7% (Di Bisceglie, 1997; Liang et al., 2000). Clearly, viral hepatitis B and C represent major public health problems and it is also worth noting that the number of deaths due to viral hepatitis is approximately 1 million per year, when death due to non-HCC viral causes are taken into account. Although there are certainly similarities between the pathogenesis, biology and even molecular biology of chronic HBV and HCV, these are two distinct viruses making the degrees of clinical similarity all the more striking. Natural history of HBV HCV infection Both HBV and HCV infection in people is characterized by the ability to cause either acute infection that is frequently clinically inapparent or an unresolved, long- term persistence (Lok et al., 2001). In either outcome, the liver is the primary site of replication. ‘Acute’ infections of adults are usually inapparent, although in some cases (perhaps fewer than 1%) a severe life- threatening hepatitis occurs (Lok et al., 2001). As implied, for both HBV and HCV, symptoms associated with long-term (chronic) infection may not be apparent for years but eventually present as fatigue, malaise and other conditions typical of hepatitis (Lok et al., 2001). The long continuum from infection, through chronicity and disease, is shown in Figure 4. Cirrhosis and primary liver cancer, as mentioned, often follow, and may be the *Correspondence: TM Block, Department of Molecular Pharmacol- ogy and Biochemistry, Jefferson Center for Biomedical Research of Thomas Jefferson University, 700 East Butler Ave., Doylestown, PA 18901, USA; E-mail: tim.block@mail.tju.edu Oncogene (2003) 22, 5093–5107 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc