The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma

Abstract

Hepatitis B virus (HBV) is one of the seven known human oncogenic viruses and has adapted to coexist with a single host for prolonged periods, requiring continuous manipulation of immunity and cell fate decisions. The persistence of HBV infection is associated with the pathogenesis of hepatocellular carcinoma, and various HBV proteins have been implicated in promoting this persistence. The precursor of hepatitis e antigen (HBeAg), is translated from the precore/core region and is post-translationally modified to yield HBeAg, which is secreted in the serum. HBeAg is a non-particulate protein of HBV and can act as both a tolerogen and an immunogen. HBeAg can protect hepatocytes from apoptosis by interfering with host signalling pathways and acting as a decoy to the immune response. By evading the immune response and interfering with apoptosis, HBeAg has the potential to contribute to the hepatocarcinogenic potential of HBV. In particular, this review summarises the various signalling pathways through which HBeAg and its precursors can promote hepatocarcinogenesis via the various hallmarks of cancer.

Keywords: HBeAg; hepatitis B virus; hepatocellular carcinoma.

Figure 3

The role of HBeAg in immune evasion: influence of HBeAg on different components of the immune system that HBeAg can influence: macrophages, monocytes, miRNA expression, and JAK/TYK/STAT signalling. 1. Macrophages—exposure of macrophages to HBeAg can influence the type of macrophage polarisation Kupffer cells undergo [84]. In addition, HBeAg can influence macrophages by decreasing TLR 2 [104]. 2. miRNA expression—HBeAg leads to an increase in miRNA-212-3p and miRNA-155, which leads to a decrease in inflammatory cytokines and immune evasion [85,87]. 3. Exposure of PBMCs monocytes to HBeAg resulted in an increase in mMDSCs, the expression of IL-6 and IL-1β, and reduced proliferation of CD4+ and CD8+ T cells [100]. 4. JAK/TYK/STAT pathway—HBeAg can influence the JAK/TYK/STAT pathway via two mechanisms to decrease response to INF therapy. In the first mechanism, the HBeAg precursor p22 blocked the nuclear translocation of pSTAT1 by interacting with Kα1, thus impeding JAK/TYK/STAT signalling [111]. In the second mechanism, mature HBeAg activates, which represses STAT1 phosphorylation, thus impeding JAK/TYK/STAT signalling [112]. Image created using biorender.com.

Figure 4

The role of HBeAg in Apoptosis: the role of HBeAg and its precursors in extrinsic and intrinsic apoptotic pathways. Extrinsic pathway: HBeAg inhibits Fas/FasL and TRAIL/DR systems which leads to the down-regulation of Fas death receptors, DR4 and DR5, expression to promote the survival of HBV infected hepatocytes [148]. Intrinsic pathways: (a) P53 pathway—p22 interacts with NUMB, which regulates Notch and MDM2 preventing ubiquitination and degradation of p53 and impairing the stability and transcriptional activity of p53 [128]; (b) G1862T mutation—G1862T mutation results in the accumulation of p25 in the ER, decreasing the activity of the PERK and IRE1/XBP1 while increasing the activity of the ATF6 receptor pathways. This results in a decrease in UPR to promote survival of HBV infected hepatocytes [122]. Image created using biorender.com.

Figure 5

Role of HBeAg in proliferative signalling pathways: the role of the HBeAg Rb gene pathway and the wnt signalling pathway. Rb gene pathway—HBeAg upregulates miR-106b, which targets the Rb gene. Thus, reducing Rb gene expression, resulting in a promotion of progression from the G0/G1 phase into the S phase of the cell cycle in Huh7 cells, adapted with permission from [162], Scientific reports (http://creativecommons.org/licenses/by/4.0/, accessed on 23 March 2023). Wnt signalling pathway—p22 induces Fzd7 and GLUL and is able to increase TCF/β-catenin transcription on its own to promote proliferative signalling [155]. Image created using biorender.com.

Figure 1

Hallmarks of cancer: HBeAg associated hallmarks of cancer are indicated in blue. Image created using biorender.com.

Figure 2

Biogenesis of HBeAg and its precursors. HBeAg and HBcAg translations from the preCore/Core ORF, adapted with permission from [50], © 2021 American Society for Microbiology. Image created using biorender.com.