Unique Features of Hepatitis B Virus-Related Hepatocellular Carcinoma in Pathogenesis and Clinical Significance

Abstract

Hepatitis B virus (HBV) infection is one of the important risk factors for hepatocellular carcinoma (HCC) worldwide, accounting for around 50% of cases. Chronic hepatitis B infection generates an inflammatory microenvironment, in which hepatocytes undergoing repeated cycles of damage and regeneration accumulate genetic mutations predisposing them to cancer. A striking male dominance in HBV-related HCC highlights the influence of sex hormones which interact with viral factors to influence carcinogenesis. HBV is also considered an oncogenic virus since its X and surface mutant proteins showed tumorigenic activity in mouse models. The other unique mechanism is the insertional mutagenesis by integration of HBV genome into hepatocyte chromosomes to activate oncogenes. HCC survival largely depends on tumor stages at diagnosis and effective treatment. However, early diagnosis by the conventional protein biomarkers achieves limited success. A new biomarker, the circulating virus-host chimera DNA from HBV integration sites in HCC, provides a liquid biopsy approach for monitoring the tumor load in the majority of HBV-HCC patients. To maximize the efficacy of new immunotherapies or molecular target therapies, it requires better classification of HCC based on the tumor microenvironment and specific carcinogenic pathways. An in-depth study may benefit both the diagnosis and treatment of HBV-related HCC.

Keywords: circulating tumor DNA; hepatitis B virus (HBV); hepatocellular carcinoma (HCC); inflammation; sex hormone; virus integration.

Figure 1

Illustration of the positive feedback loop between HBx and AR for promotion of HBV-induced hepatocarcinogenesis in male CHB patients. In male HBV carriers with chronic infection, HBx enhances the transcriptional activity of androgen-activated AR, which recognizes the androgen-responsive element (ARE) motifs within viral enhancer I (Enh I), thus reinforcing overall HBV gene expression including HBx (the right part). On the other hand, the HBx-activated AR could aberrantly stimulate downstream expression of proto-oncogenes, which facilitate cell proliferation and survival in the carcinogenic process. This positive feedback circuitry may simultaneously elevate serum HBV titer and activate host genes with carcinogenic potentials in infected hepatocytes, leading to the elevated risk of HCC development in male CHB patients.

Figure 2

Insertional mutagenesis by integration of HBV genome predisposes potential genetic changes for selective clonal expansion in HCC development. After HBV infection, random integration of viral genome may occur (about 0.1%) in infected hepatocytes. The genetic cis and trans-regulatory effects derived from integrated HBV sequences may render the hepatocytes obtain a growth advantage. From CHB stage to cirrhotic phase, the repeated cycles of cell damage and hepatocyte regeneration may predispose the accumulation of other genetic changes. Therefore, this chronic inflammatory microenvironment sets up a scenario that promotes the hepatocytes with advantageous HBV insertional mutagenesis for clonal expansion and eventually selects for HCC formation.