Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update

Figure 1 A schematic overview shows the impacts of hepatitis B virus and hepatitis C virus proteins in the Wnt signaling pathway. In an inactive state, cytoplasmic β-Catenin interacts with a multiprotein degradation complex comprised of CK1a, APC, GSK3β, and Axin, and following phosphorylation, is targeted for proteasome-dependent degradation. On binding Wnt ligands to FZD and LRP5/6 receptors, the scaffolding protein DVL is recruited to the membrane and phosphorylates GSK3β leading to the disassembly of the β-Catenin destruction complex. This event results in the rescue of β-Catenin from proteasomal degradation leading to its accumulation in the cytoplasm and eventually allowing its translocation to the nucleus. Consequently, β-Catenin activates the transcription of target genes through interaction with TCF and LEF family members. Wnt signaling is regulated by secreted proteins, including SFRPs and DKKs, which inhibit Wnt signaling by binding to FZD and LRP5/6 receptors, respectively. Independent of its transcriptional activity, β-Catenin, forming a complex with E-cadherin, also facilitates cellular junctions between cells. The disintegration of E-cadherin production causes the dissociation of the complex and subsequent internalization of β-Catenin, ending with activation of its target genes. Hepatitis B virus and hepatitis C virus proteins deregulate the expression of various components of the Wnt/β-Catenin pathway and contribute to tumor development and behavior. APC: Adenomatous polyposis coli; CK1: Casein kinase 1a; DKK: Dickkopf family of proteins; DVL: Disheveled segment polarity protein; FZD: Frizzled family of the receptor; GSK3b: Glycogen synthase kinase–3b; LEF: Lymphoid enhancing factor; Lrp5/6: LDL receptor-related protein 5/6; SFRPs: Secreted frizzled-related protein; TCF: DNA-bound T-cell factor; ⊥: Inhibition.