Hepatitis Virus and Hepatocellular Carcinoma: Recent Advances

Abstract

Hepatocellular carcinoma (HCC) remains a global health challenge, causing 600,000 deaths each year. Infectious factors, including hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV), have long been considered the major risk factors for the development and progression of HCC. These pathogens induce hepatocyte transformation through a variety of mechanisms, including insertional mutations caused by viral gene integration, epigenetic changes, and the induction of long-term immune dysfunction. The discovery of these mechanisms, while advancing our understanding of the disease, also provides targets for new diagnostic and therapeutic approaches. In addition, the discovery and research of chronic HEV infection over the past decade indicate that this common hepatitis virus also seems to have the potential to induce HCC. In this review, we provide an overview of recent studies on the link between hepatitis virus and HCC, as well as new diagnostic and therapeutic approaches to HCC based on these findings. Finally, we also discuss the potential relationship between HEV and HCC. In conclusion, these associations will further optimize the diagnosis and treatment of infection-associated HCC and call for better management policies.

Keywords: diagnosis; hepatitis virus; hepatocellular carcinoma; molecular mechanism; treatment.

Figure 3

Management and treatment of HBV-induced HCC. (a) The main measures before HCC are active HBV vaccination and the continuous detection of the progression of liver fibrosis. For patients with chronic HBV infection, antiviral therapy should be actively carried out to prevent the further development of viral hepatitis. Chronic HBV infection refers to an HBV-positive test, the course of the disease being more than half a year or the onset date not being clear, and clinical manifestations of chronic hepatitis [94]; (b) The treatment of HCC includes surgical and non-surgical methods. The surgery includes liver resection and liver transplantation. Non-surgical methods include radiofrequency local ablation, chemotherapy, and radiotherapy [88]; (c) Systemic therapies, including immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors (TKIs), monoclonal antibodies (McAbs) and other targeted molecular drugs, can better achieve personalized treatment, especially to improve the survival rate of advanced patients who cannot be treated with surgery. The image material is referenced from Biorender [2].

Figure 1

Pathogenesis of infection-induced hepatocellular carcinoma. Infectious factors include HBV, HCV and HDV, which mainly mediate chronic inflammation and persistent immune response through chronic viral hepatitis, leading to liver fibrosis and cirrhosis, inducing somatic mutations, and eventually leading to HCC. HBV infection is a major infectious factor with a unique oncogenic mechanism. HBV can cause cancer-related gene mutations through gene integration and epigenetic changes and promote the occurrence of HCC. Other virus-related risk factors include high viral load, viral gene mutations and high-risk genotypes. Environmental and host-related factors play a synergistic role. The figure material is referenced from Biorender.

Figure 2

HBV DNA integration plays a very important role in HBV-induced HCC pathogenesis and can lead to insertional mutations in cancer-related genes. Among them, the most common site of HBV-mediated insertional mutation is located in the TERT promoter. (a) Common HBV DNA integration sites in HCC patients. The pie chart shows the distribution of TERT genomic alterations detected in the HCC cohort; (b) Schematic illustration showing frequent TERT HBV integration and its genomic location in human HCC tissues. After HBV integration in human HCC, the direct linkage of HBV EnhI and HBx DNA sequences to the human TERT promoter leads to TERT activation and telomerase overexpression, promoting cancer development. Reprinted with permission from Ref. [42]. 2020, John Wiley and Sons.