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

Table 3 Molecular pathways of hepatocellular carcinoma carcinogenesis in hepatitis B virus infected patients

HBx related pathways
DNA repair impairment and DNA instability
HBx - binds to DDB1 - instability of Scm5/6 - impairment in DNA replication and repair
HBx - interacts with TFIIH - impairment in DNA replication and repair
HBx - blocks BER pathway - impairment in DNA repair
HBx - binds to CRM1 and sequestering it in cytoplasm - aberrant centrosome duplication and chromatin’s segregation - chromosome instability
DNA replication increase
HBx - upregulates RLF and CDT1 and downregulates geminin - DNA replication
HBx - binds to cccDNA - recruiting PCAF - histone H3 acetylation - inhibition of chromatin’s methylation - DNA replication
Cell cycle deregulation via signal pathways
HBx - binds to p53 - impaired function of p53 - cell cycle dysregulation
HBx - induces AFP expression - activation of PTEN and PI3K/mTOR pathway - cell cycle deregulation
HBx - activates Notch1 and Notch4 receptor - cell cycle progression
HBx - upregulates NF-kB, AP-1, AP-2, c-EBP, RNA-polymerase, ATF - altered oncogenes expression and cell cycle deregulation
HBx - upregulates NF-kB - upregulation of EGR1 - upregulation of miR-3928v - downregulation of VDAC3 - tumor suppressor inhibition
HBx - downregulates SFRP1 and SFRP5 - DNMT1 recruitment - inhibition of WNT/β-catenin pathway - epithelial mesenchymal transition
Epigenetic modification impairment
HBx - interacts with MBD2 and CBP - P3 and P4 promoters’ activation through hypomethylation - recruitment of IGF2 - oncogenesis
HBx - stimulates deacetylation of IGFBP3 gene - upregulation of IGF1 - mitogenic and anti-apoptotic effects
HBx - upregulates DNMT1 - hypermethylation of RASSF1A - tumor suppressor inhibition
HBx - downregulates DNMT3a/DNMT3L and recruits HDAC1 - hypomethylation of oncogenes promoters including JAK/STAT3 - impairment in cell differentiation
HBx - downregulates CD82, MTA1, PCDH10 through hypermethylation - tumor progression
HBx - inhibits CDH1 through deacetylation - E-cadherin upregulation - metastasis promotion
Apoptosis impairment
HBx - upregulates Bcl2 and Mcl1, inhibits Bax - apoptosis inhibition
HBx - upregulates Foxo4 - increased resistance to ROS damage, avoiding cell death and apoptosis
HBx - upregulates NF-kB - increase of DR5 - TRAIL induced apoptosis
HBx - inhibits caspase-8 inhibitor A 20 - TRAIL induced apoptosis
mi/lnc RNA related pathways
HBx - impairs miRNA regulation and synthesis - cell cycle deregulation
HBx - impairs lncRNA regulation and synthesis - cell cycle deregulation
Oxidative stress
HBx - downregulates NQO1 - mitochondrial injury - ROS production
C-terminal truncated HBx - mitochondrial DNA damage - ROS production
Neoangiogenesis
HBx - upregulates VEGF, HIF1 and ANG2 - neoangiogenesis
Unknown mechanism
HBx - binds to HSP60 and HSP70 - unknown function but involved in HCC carcinogenesis
Pre-S/S related pathways
pre-S2 - retention of HBV proteins in ER - ROS increase - cell DNA damages
pre-S2 - retention of HBV proteins in ER - upregulation of CCNA - chromosome instability and centrosome overduplication
pre-S2 - interacts with JAB1 - RB tumor suppressor inhibition
HBsAg related pathways
HBsAg - binds to ECHS1 - ROS increase - cell DNA damages
HBsAg - binds to JTB - decreased apoptosis and increased cell mobility
HBeAg related pathways
HBeAg - stimulates upregulation of miR-106b - RB tumor suppressor inhibition
HBV DNA related pathways
cccDNA - triggers DNA repair pathways - histone degradation and cell cycle checkpoints activation - enhanced DNA recombination rate
HBV DNA - genome integration - oncogene activation or tumor suppressor inhibition with evidence of fusion proteins
HBV DNA - genome integration - genetic instability - clonal proliferation
Inflammatory pathways
Increased cytokines production (TGF-β, IL-4, IL-10, IL-12, IL-13) - JAK/STAT3 activation - cell proliferation
CD4+ T follicular helper decrease - loss of growth inhibition and death control of cancer cells
CD8+ cell dysfunction - impaired growth inhibition and death control of cancer cells
Functional exhausted CD8+TIM-3+ T cells - increased viral replication - increased viral factors in HCC development
NK cells - increase in IL-4 and IL-13 - activation of HSCs - increased cytokines production - cell cycle deregulation
NK cells - miR-146a increase - reduced cytotoxicity and decreased IFN-γ production - reduction in immunosurveillance
Tregs - PD1 and CTLA4 overexpression - C
Gut microbiota-related pathways
HBV related dysbiosis - circulating LPS - TLR4 activation - cytokines production - JAK/STAT3 activation - cell proliferation

DDB: Damage specific DNA binding protein; Scm5/6: Structural maintenance of chromosomes 5/6; TFIIH: Transcription factor II H; BER: Base excision repair; RLF: Rearranged L-Myc fusion gene protein; cccDNA: Covalently closed circular DNA; PCAF: P300/CBP-associated factor; AFP: Alpha fetoprotein; PTEN: Phosphatase and tensin homolog; PI3K: Phosphatidylinositol 3-Kinase; mTOR: Mechanistic target of rapamycin kinase; NF-kB: Nuclear factor-kappa B; AP-1: Activator protein 1; ATF: Activating transcription factor; EGR1: Early growth response protein 1; VDAC: Voltage dependent anion channel; SFRP: Secreted frizzled-related protein; DNMT: DNA methyltransferase; WNT: Wingless-related integration site; MBD: Methyl-CpG binding domain protein; CBP: CREB binding protein; IGF: Insulin like growth factor; IGFBP: Insulin like growth factor binding protein; MTA: Metastasis associated; Bcl2: B-cell lymphoma 2; Mcl1: Myeloid cell leukemia-1; PCDH: Protocadherins; miRNA: Micro-RNA; lncRNA: Long non coding RNA ; ROS: Reactive oxygen species; HIF: Hypoxia-inducible factor; ANG: Angiogenin; VEGF: Vascular endothelial growth factor; HSP: Heat shock protein; HCC: Hepatocellular carcinoma; ER: Endoplasmic reticulum; CCNA: Cytoplasmatic Cyclin A; RB: Retinoblastoma; ECHS: Enoyl-CoA hydratase short chain; JTB: Jumping translocation breakpoint; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B Virus; TGF: Transforming growth factor; IL: Interleukin; NK: Natural killer; HSC: Hematopoietic stem cells; IFN: Interferon; PD1: Programmed cell death 1; CTLA4: Cytotoxic T-lymphocyte antigen 4; LPS: Lipopolysaccharides; TLR4: Toll-like receptor 4.