Molecular Carcinogenesis of HBV-Related HCC
Primary liver cancer is the second most common cause of death due to cancer worldwide, and a vast majority of primary liver cancer is the hepatocellular carcinoma (HCC) subtype. Although a number of etiologies are recognized to cause HCC, HBV infection ac
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Molecular Carcinogenesis of HBV-Related HCC Valerie Fako and Xin W. Wang
Abstract
Primary liver cancer is the second most common cause of death due to cancer worldwide, and a vast majority of primary liver cancer is the hepatocellular carcinoma (HCC) subtype. Although a number of etiologies are recognized to cause HCC, HBV infection accounts for over 50% of diagnosed HCC cases. HBV infection leads to the development of HCC through a variety of mechanisms. Indirectly, viral infection leads to repetitive liver injury through oxidative stress, the immune response, and telomere shortening, eventually causing cellular transformation. Integration of viral DNA into the host genome can indirectly lead to carcinogenesis by inducing genomic instability, as well as directly causing oncogenesis by preferentially integrating into genomic loci of known oncogenes. The activity of the HBV X protein (HBx) has been demonstrated to directly promote transformation and hepatocarcinogenesis in a number of ways, including activating cancer-related pathways and altering cellular epigenetic and noncoding RNA expression. In this chapter, we will summarize the current scientific knowledge of the ways in which HBV infection can lead to HCC. Keywords
Hepatocellular carcinoma • Hepatocarcinogenesis • Liver injury • Viral DNA integration • HBx protein
V. Fako • X.W. Wang (*) Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2018 J.-H. Kao, D.-S. Chen (eds.), Hepatitis B Virus and Liver Disease, https://doi.org/10.1007/978-981-10-4843-2_8
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V. Fako and X.W. Wang
Introduction
Globally, primary liver cancer represents the fifth most commonly diagnosed cancer and the second most common cause of death due to cancer (Theise 2014). Hepatocellular carcinoma (HCC) accounts for a majority (85–90%) of primary liver cancers and leads to an estimated 600,000 deaths per year (Jemal et al. 2011). Geographically, the incidence of HCC is not distributed equally, with greater than 80% of HCC cases occurring in East Asia or sub-Saharan Africa. China alone accounts for over 50% of global HCC cases (El-Serag 2012). There are a number of recognized etiologies leading to the development of HCC including liver cirrhosis, alcoholic liver disease, exposure to aflatoxin B1, diabetes, and obesity. However, the main etiology of HCC is hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (Sanyal et al. 2010). The association between HCC development and chronic HBV infection was first reported in 1975 (Blumberg et al. 1975). Chronic HBV infection is now recognized to account for over 50% of HCC cases worldwide. Over 350 million people are chronic HBV carriers, with 75% of these cases occurring in Asian countries. Prospective cohort studies have shown that people who are chronically infected with HBV have a 5- to 100-fold increased risk of developing HCC compared to non-infected persons. (El-Serag 2012). Most cases of HCC caus
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