Fig. 2.

Wnt/β-catenin signaling is activated by hepatitis C virus (HCV) proteins. HCV core protein elevates gene expression of Wnt ligands, frizzled (FZD) receptor, and low-density lipoprotein receptor related protein 5/6 (LRP5/6) but decreases the expression of the Wnt antagonists dickkopf (DKK) and secreted frizzled-related protein (SFRP) by recruiting DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) to their transcription start sites. In addition, HCV core protein releases β-catenin from the β-catenin–E-cadherin complexes by suppression of the CDH1 gene promoter (which encodes E-cadherin). NS5A protein activates phosphoinositide 3-kinase (PI3K)/Akt signaling, leading to the inactivation of glycogen synthase kinase 3β (GSK3β) and subsequent reduced breakdown of β-catenin, or directly stabilizes β-catenin. The overall effect is the cytoplasmic accumulation of β-catenin and stimulation of downstream transcription