Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment

Table 5 Molecular pathways of hepatocellular carcinoma carcinogenesis in hepatitis D virus infected patients

Cell cycle deregulation via signal pathways
L-HDAg - Smad 3 activation - TGFβ upregulation - cells growth and dedifferentiation
L-HDAg - antagonizes c-Jun inhibitory effect over TGFβ - TGFβ upregulation - cells growth and epithelial-mesenchymal transition
L-HDAg - TNF-α stimulation - NF-κB activation - inflammation and proliferation
L-HDAg - activates STAT3 downstream protein - JAK/STAT pathway activation - cell growth
L-HDAg - stimulates c-Fos activation - cells growth and dedifferentiation
L-HDAg - downregulates GSTP1 - tumor oncosuppressor inhibition
Oxidative stress
L-HDAg - NF-κB and STAT3 activation - ROS production - DNA damage
L-HDAg - activates promoters of GRP78 and GRP94 - ROS production - DNA damage
L-HDAg - activates TGFβ1 - Nox4 activity - ROS production - DNA damage
S-HDAg and L-HDAg - increase in TRAF2 - inflammation and ROS production
S-HDAg and L-HDAg - bind to SRE - targeting proinflammatory genes - inflammation and ROS production
Epigenetic mechanisms
S-HDAg and L-HDAg - increased activity of histone acetyltransferases and CBP - histone H3 acetylation of clusterin promoter - increased clusterin expression - prolonged cell survival
S-HDAg - stimulates Histone H1e acetylation - clusterin promoter activation - prolonged cell survival
HDV - DNMT1 and 3b increased activity - tumor suppressor inhibition
S-HDAg and L-HDAg - hypermethylation of E2F1 promoter - cell cycle dysregulation

HDAg: Hepatitis D virus antigen; Smad3: Small mother against decapentaplegic 3; TGF: Transforming growth factor; TNF: Tumor necrosis factor; NF-kB: Nuclear factor-kappa B; GSTP: Glutathione S-transferase Pi; ROS: Reactive oxygen species; GRP: Gastrin releasing peptide; HDV: Hepatitis D virus; STAT3: Signal transducer and activator of transcription 3; SRE: Stress response element; Nox4: NADPH oxidase; TRAF: Tumor necrosis factor-receptor associated factor; CBP: CREB-binding protein; DNMT1: DNA methyltransferases 1; JAK: Janus kinase.