Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma

Abstract

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.

The Dark Side of the Force: When the Immune System Is the Fuel of Tumor Onset

“…Only HBV has a direct effect on host cell DNA; in fact, cirrhosis was not found in all the HBV-positive tumors [ 165 ]. In contrast, the tumor-promoting effect of HCV is linked only to its ability to induce chronic inflammation [ 166 ].…”

“…Common mechanisms of action used by hepatitis viruses involve both viral and immune agents: several viral proteins are able to deregulate the hosts’ signaling pathways; moreover, the non-resolving inflammation caused by the viral infection results in immune-mediated stress damage, which leads, together with viral proteins, to intracellular oxidative stress [ 166 ].…”

“…HBV is not curable, but it has been almost eradicated after vaccine introduction; however, it remains a problem in those countries in which the vaccine is still not available, such as Eastern Asia. The tumor onset mechanisms of HBV are two: on the one hand, HBV DNA is able to integrate directly into the host DNA; on the other hand, HBV is able to establish chronic infection [ 166 ]. The chronic hepatitis phase is characterized by the increased adaptive immune response and a reduction of HBV DNA levels; as a consequence, there is a release of ROS and cytokines that induces immunosuppression.…”

Virus-Mediated Cell-Cell Fusion

“…Hepatitis C virus (HCV) is an enveloped virus belonging to the Hepacivirus genus of the Flaviridae family [ 219 ], and its genome is a 10 kb monopartite, linear, positive single-stranded RNA. HCV primarily infects human hepatocytes, causing chronic hepatitis, hepatic cirrhosis, and hepatocellular carcinoma [ 220 ]. During replication, the viral RNA is translated into a polyprotein and then processed into three structural proteins, including the Envelope glycoproteins E1 and E2 which form a E1/E2 heterodimer, and seven nonstructural proteins [ 221 ].…”

Reciprocal Inhibition of Immunogenic Performance in Mice of Two Potent DNA Immunogens Targeting HCV-Related Liver Cancer

“…Examples are synthetic peptides derived from conserved regions of core in IC41 [ 9 ], DNA encoding HCV core and envelope E1 and E2 proteins in CIGB-230 [ 10 ], and recombinant HCV core produced in yeast cells in GI-5005 [ 11 ]. Interestingly, they included HCV core, a protein with plentitude of adverse properties including interference with several metabolic pathways and gene regulation cascades, modulation of apoptosis, with potential to promote cell growth and immortalization, and regulate the immune response [ 12 , 13 , 14 ]. Despite the adverse properties of HCV core, Drane et al showed that a candidate HCV vaccine based on the recombinant HCV core protein with ISCOMATRIX™ adjuvant was safe and immunogenic, inducing T cell response with cytokine production and production of antibodies in preclinical and clinical trials [ 15 ].…”