Mechanisms of Hepatitis B Virus-Induced Hepatocarcinogenesis
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in nearly 1 million deaths every year. Many of these patients die fr
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Introduction to Hepatitis B Virus
Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases, including acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). There are approximately 250 million people worldwide suffering from chronic HBV infection, resulting in nearly one million deaths annually (Iloeje et al. 2006; Kao and Chen 2002; WHO 2017). Most chronic HBV carriers in endemic areas such as sub-Saharan Africa and China acquired the virus from their carrier mothers early in life, although HBV can also be transmitted via other pathways such as sex or the sharing of injection needles (Milich and Liang 2003; Shin et al. 2016; Ou 1997). Due to the lack of an effective treatment, HBV remains one of the most serious health problems. The infection by HBV contributed to slightly more than 50% of HCC cases worldwide in a 2002 study, rendering it the most important carcinogenic factor of HCC (Parkin 2006). HBV can induce HCC via the induction of chronic liver inflammation, which can cause oxidative DNA damage, liver injury and regeneration, and eventual oncogenic transformation of hepatocytes. Factors like age, gender, duration of infection, alcohol consumption, and the exposure to carcinogens such as aflatoxin can also increase the risk of HCC for HBV patients. In this chapter, we will focus on the direct effect of HBV on hepatocytes in the induction of hepatocarcinogenesis.
J. Lee K.-N. Tsai J. J. Ou (&) Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA 90033, USA e-mail: [email protected] © Springer Nature Switzerland AG 2021 T.-C. Wu et al. (eds.), Viruses and Human Cancer, Recent Results in Cancer Research 217, https://doi.org/10.1007/978-3-030-57362-1_3
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1.1 HBV Genome and Lifecycle HBV belongs to the Hepadnaviridae family (Liang 2009; Tiollais et al. 1985). It is an enveloped virus with a partially double-stranded and circular DNA genome of approximate 3.2 Kb. The HBV genome is remarkably compact and encodes four overlapping genes named C, P, S, and X. The C gene codes for the 21-kDa core protein, which forms the viral core particle that displays the core antigenic determinant (i.e., the core antigen, HBcAg) (Tsai et al. 2018), and a related 25-kDa protein termed the precore protein. The precore protein contains the entire sequence of the core protein plus an amino-terminal extension of 29 amino acids (i.e., the “precore sequence”) (Ou 1997; Ou et al. 1986). The first 19 amino acids of the precore protein serve as a signal peptide that directs the precore protein to the endoplasmic reticulum (ER) where it is removed by the signal peptidase to generate the 22-kDa precore protein derivative. This precore protein derivative is subsequently cleaved at its carboxy terminus at multiple sites by the furin-like protease in the Golgi and secreted (Ito et al. 2009). The secreted precore protein derivatives are known as the e antigen (i.e., HBe
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