Mechanisms of HBV-related hepatocarcinogenesis

Abstract

The hepatitis B virus (HBV) is a small enveloped DNA virus, which primarily infects hepatocytes and causes acute and persistent liver disease. Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma, but the molecular mechanisms underlying virally-induced tumourigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, indirect roles have been proposed, including insertional activation of cellular cancer-related genes by HBV DNA integration, induction of genetic instability by viral integration or by the regulatory protein HBx, and long-term effects of viral proteins in enhancing immune-mediated liver disease. Recent genetic studies indicate that HBV-related tumours display a distinctive profile with a high rate of chromosomal alterations and low frequency of beta-catenin mutations. This review will discuss the evidence implicating chronic HBV infection as a causal risk factor of primary liver cancer. It will also discuss the molecular mechanisms that are critical for the tumourigenic process due to long lasting infection with HBV.

Molecular Signatures of Environmental Mutagens in Hepatocellular Carcinoma

“…HBV genome integration has been associated with host DNA micro-deletions in genes such as telomerase reverse transcriptase (TERT), platelet-derived-growth-factor receptor-b (PDGFRb) or mitogen activated protein kinase 1 (MAPK1), among others (11)(12)(13)(14). Second, the viral oncoprotein HBx interacts with many cell factors and modulate their activity, including components of SRC, RAS, RAF, MAPK, ERK, JNK and NF-kappaB signaling cascades (15)(16)(17). Third, HBx binds and perhaps inactivates the tumor suppressor protein p53, therefore increasing cellular proliferation and survival and compromising DNAdamage checkpoints (16,18,19).…”

Hepatitis B virus X protein induces epithelial–mesenchymal transition by repressing E-cadherin expression via upregulation of E12/E47

“…Hepatitis B virus (HBV) is strongly associated with the development of hepatocellular carcinoma (HCC) (Neuveut et al, 2010;Xu et al, 2014). One of the ORFs encoded by the HBV genome is an oncogenic X protein (HBx), which is the most frequently integrated viral sequence found in HCC (Paterlini et al, 1995).…”

“…One of the ORFs encoded by the HBV genome is an oncogenic X protein (HBx), which is the most frequently integrated viral sequence found in HCC (Paterlini et al, 1995). HBx is likely to be implicated at several different steps of HCC development (Neuveut et al, 2010;Xu et al, 2014). Although most efforts in the study of the role of HBx have focused on its involvement in the genesis of HCC, it is also involved in tumour progression, invasion and metastasis.…”

Combined effects of p53 and MDM2 polymorphisms on susceptibility and surgical prognosis in hepatitis B virus-related hepatocellular carcinoma

“…The risk of HCC is increased in patients with higher levels of HBV replication, determined by tests for hepatits B e antigen (HBeAg) and levels of HBV DNA. Over the last three decades, several mechanisms have been described for the role of HBV in causing HCC including HBV DNA integration in the host genome or transactivation of oncogenes of the host by HBV X protein (HBx) or by another truncated protein derived from the pre-S2/S region of HBV genome (Anzola, 2004;Brechot, 2004;Neuveut et al, 2010). Indirect mechanisms have also been suggested such as HBV causing chronic hepatic injury and hepatocyte regeneration (Anzola, 2004;Brechot, 2004;Neuveut et al, 2010).…”