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

Table 6 Molecular pathways of hepatocellular carcinoma carcinogenesis in hepatitis C virus infected patients

HCV core protein-related pathways
Signaling pathways
HCV core protein - binds p53, p73 and RB - tumor suppressors inactivation
HCV core protein - increased TERT gene activity – oncogenesis
HCV core protein - induces expression of cyclin E/CDK2 - G1/S transition
HCV core protein - inhibits CKI1 - cell cycle deregulation
HCV core protein - induces RAF/MAPK pathway – oncogenesis
HCV core protein - inhibits E-cadherin expression and SFRP1 via histone modification - activation of WNT/β-catenin signaling - epithelial mesenchymal transition
HCV core protein - interacts with TBR1 - inhibit TGFβ signaling and prevent translocation of Smad - cell spreading, cell growth regulation
Oxidative stress and mitochondrial impairment
HCV core protein - impairs lipid β-oxidation - reduces mitochondrial electron transport chain - ROS production
HCV core protein - impairs mitophagy - mitochondrial damage - ROS production
HCV core protein -interacts with HSP60 - ROS production and inhibition of TNFα induced apoptosis
Angiogenesis
HCV core protein - stimulate an increasing in HIF1α and AP-1 - upregulation of VEGF expression - angiogenesis
HCV core protein - activates PI3K/Akt and JAK/STAT - AR activation - angiogenesis
HCV core protein - activates COX2, MMP-2 and MMP-9 – angiogenesis
Inflammation
HCV core protein - suppresses of NF-kB pathways - impaired immune response
HCV core protein - upregulates cytokines and deregulates HSCs activity - impaired immune response
E2 protein-related pathways
E2 protein - interacts with CD81 - impaired host immune system
E2 protein - activates MAPK/ERK pathway - promoting cell proliferation
E2 protein - inhibits PKR - inhibition of protein synthesis
NS2 protein-related pathways
NS2 - activates cyclinD/CDK4 - induces expression of cyclin E/CDK2 - G1/S transition
NS2 - binds p53 - tumor suppressors inactivation
NS3-related pathways
NS3 - inhibits p53 - tumor suppressor inactivation
NS3 - inhibits ATM - tumor suppressor inactivation
NS3 - suppresses of NF-kB pathways - impaired immune response
NS3 - blocks TLR3 and RIG-I - impaired immune response
NS5A-related pathways: Signaling pathways
NS5A - inhibits p53 - tumor suppression inactivation
NS5A - interacts with TGFBR1 - inhibit TGFβ signaling and prevent translocation of Smad 3/4 - cell spreading, cell growth regulation
NS5A - increases phosphorylation of GSK3β - activates β-catenin - upregulates c-Myc - cell growth
NS5A - activates Akt pathway – oncogenesis
NS5A - interacts with PI3K p85 subunit - upregulates cell survival cascade
NS5A - activates Twist 2 - epithelial mesenchymal transition
NS5A - activates RAS - enhance tumor cell invasiveness
NS5A - inhibits JAK/STAT pathway - blockage of IFN signaling
NS5A - inhibits PKR - inhibition of protein synthesis
NS5A - activates TLR4 - amplified NANOG - Twist 1 induction - oncogenesis and epithelial mesenchymal transition
NS5A-related pathways: Apoptosis
NS5A - inhibits TNFα mediated apoptosis - cell immortalization
NS5A - inactivates caspase 3 - inhibition of apoptosis
NS5A - inhibits proteolytic cleavage of death substrates (PARPs pathway) - impaired DNA repair and apoptosis
NS5A-related pathways: Oxidative stress
NS5A - induces of WNT/β-catenin signaling - upregulation of c-Myc - ROS production
NS5A - increases calcium release from ER - mitochondrial calcium uptake - ROS production
Epigenetic modifications
HCV - alters histone mark H3K27ac - TNFα and IL2 pathways - cell growth deregulation and epithelial mesenchymal transition
HCV - upregulates DNMT1 and SMYD3 - increased methylation of CDKN2A, GSTP1, APC, SOCS1, RASSF1A - tumor suppressors inhibition
HCV - increases miR-141 - inhibition of DLC1 - tumor suppressor inhibition
Inflammatory pathways
HCV - activates CCL20-CCR6 - endothelial cell invasion and angiogenesis
Switch from Th1 to Th2 - increasing in IL4-5-8-10 - loss of death control on cancer cells
Switch from Th1 to Th2 - decreasing in IL1-2-12-15 - loss of death control on cancer cells
Gut microbiota-related pathways
HCV-related dysbiosis - circulating LPS - TLR4 activation - cytokines production - JAK/STAT3 activation - cell proliferation

HCV: Hepatitis C virus; RB: Retinoblastoma; TERT: Telomerase reverse transcriptase; MAPK: Mitogen-activated protein kinase; SFRP: Secreted frizzled-related protein; WNT: Wingless-related integration site; TBR1: T-Box brain transcription factor 1; TGF: Transforming growth factor; Smad: Small mother against decapentaplegic; ROS: Reactive oxygen species; HSP60: Heat shock protein 60; TNF: Tumor necrosis factor; HIF: Hypoxia-inducible factor; AP-1: Activator protein 1; VEGF: Vascular-endothelial growth factor; PI3K: Phosphatidylinositol 3-kinase; MMP: Matrix metalloproteinase; NF-kB: Nuclear factor-kappa B; HSC: Hematopoietic stem cells; ATM: Ataxia telangiectasia mutated; TLR: Toll-like Receptor; RIG: Retinoic acid-inducible gene; TGFBR: Transforming growth factor beta receptor; GSK: Glycogen synthase kinase; RAS: Rat sarcoma virus gene; PKR: Protein kinase R; PARP: PolyADP-Ribose polymerase; IL: Interleukin; GSTP: Glutathione S-transferase Pi; DNMT1: DNA methyltransferase 1; SMYD: SET and MYND domain-containing proteins; APC: Adenomatous polyposis coli; SOCS1: Suppressor of cytokine signaling 1; RASSF1A: RAS Association Domain Family Protein 1A; DLC1: Deleted in liver cancer 1; LPS: Lipopolysaccharides; JAK: Janus kinase; STAT3: Signal transducer and activator of transcription 3; CCL: C-C motif chemokine ligand; PARPs: Poly(ADP-ribose) polymerases; CDK4: Cyclin-dependent kinase 4; COX2: Cyclooxygenase 2; RAF: Rapidly accelerated fibrosarcoma; ANG2: Angiopoietin 2; CCR: Chemokine receptor type.