The oncogenic role of hepatitis delta virus in hepatocellular carcinoma

Abstract

Hepatitis delta virus (HDV) is a small defective virus that needs hepatitis B virus (HBV) to replicate and propagate. HDV infection affects 20-40 million people worldwide and pegylated interferon (PegIFN) is the only recommended therapy. There is limited data on the contribution of HDV infection to HBV-related liver disease or liver cancer. Evidence from retrospective and cohort studies suggests that HBV/HDV coinfection accelerates progression to cirrhosis and is associated with an increased risk of hepatocellular carcinoma (HCC) development compared to HBV monoinfection. Although the life cycle of HDV is relatively well known, there is only ancillary information on the molecular mechanisms that can drive specific HDV-related oncogenesis. No thorough reports on the specific landscape of mutations or molecular classes of HDV-related HCC have been published. This information could be critical to better understand the uniqueness, if any, of HDV-related HCC and help identify novel targetable mutations. Herein, we review the evidence supporting an oncogenic role of HDV, the main reported mechanisms of HDV involvement and their impact on HCC development.

Keywords: HCC, co-infection; Hepatitis B virus; defective; liver cancer; molecular pathogenesis; superinfection.

Graphical abstract

Fig. 1

Global distribution of HDV infection among HBsAg carriers. HDV prevalence is highly different among different countries. The most prevalent areas are Punjab, the Amazon basin, Somalia, and Mongolia. In European countries, the highest prevalences are seen in Romania and Albania. HBsAg, hepatitis B virus surface antigen; HDV, hepatitis delta virus.

Fig. 2

Potential mechanism of increased oncogenicity due to HDV. L-HDAg potentiates TGF-β and c-Jun signalling cascades. It can also activate NOX-4 and promote oxidative stress, which enhances NF-kB and STAT3 signalling. STAT3 promotes transcription of DNMT3b, which induces expression of the E2F1 transcription factor. L-HDAg potentiates NF-αB activation via TNF-α receptor by interacting with TRAF2. Finally, both L-HDAg and S-HDAg increase clusterin expression by promoting acetylation of histone 3. HDV, hepatitis delta virus; L-HDAg, large delta antigen; OS, oxidative stress; S-HDAg, small delta antigen.

Fig. 3

Natural history of HDV infection. Commonly, HDV infects hepatocytes already infected by HBV (i.e. superinfection). After that, 90% of patients will develop a chronic HBV/HDV infection with a faster evolution to cirrhosis in 10 years. Some risk factors, such as alcohol consumption or genotype 1 infection may accelerate liver disease development. HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HDV, hepatitis delta virus.