Table 1.

Summary of the function of etiological factors on the regulation of Wnt/β-catenin signaling.

Etiological Factors	Roles to Regulate Wnt/β-Catenin Signaling	References
HBV
HBx	♦Downregulation of Wnt antagonist SFRP1 and SFRP5 expression due to genetic silencing by recruiting elevated DNA methyltransferase 1 and 3A to gene promoters	[20]
	♦Disruption of the destruction complex by competitively binding APC or by inhibiting GSK3 activity through activation of Src kinase as well as induction of cell cycle-related kinase-mediated androgen receptor signaling	[21,22,23]
HBsAg	♦Overexpression of LEF-1 and β-catenin downstream c-Myc and cyclin D1	[24,25,26]
other	♦Insertion of HBV gene into a LINE1 element produces an oncogenic HBV-LINE1 chimeric transcript, inducing the nuclear localization of β-catenin.	[18,27]
HCV
core protein	♦Elevated expression levels of Wnt ligands, FZD, and LRP5/6 receptors	[33,34]
	♦Downregulated transcription of Wnt antagonists SFRP2 and DKK1	[35,36]
	♦Hypermethylation at the CDH1 promoter leading to the reduction of E-cadherin and dissociation of the β-catenin/E-cadherin complexes at the cell–cell adhesion sites	[37]
NS5A	♦Combination and stabilization of β-catenin protein	[39]
	♦Stimulation of PI3K/Akt pathway to further inactivate GSK3β	[40,41,42]
E2	♦Activation of SHP-2, promoting tyrosine dephosphorylation of parafibromin to bind and stabilize β-catenin in the nucleus	[43,44]
others	♦Upregulation of miR-155 to restrain APC expression	[45]
	♦Activation of EGFR and FGF signaling, leading to tyrosine phosphorylation of β-catenin at residue Y654 and its release from the β-catenin/E-cadherin complexes, as well as inactivation of GSK3β through PI3K/Akt and Ras/Raf/MEK/ERK cascades	[46,47]
Alcohol abuse	♦Decrease of nuclear and cytoplasmic β-catenin in liver, increasing susceptibility to alcoholic liver disease in in vivo models treated with ethanol less than 8 weeks	[53,54,55,56,57]
	♦Increase of β-catenin in non-tumorigenic hepatocytes in a mouse model fed a 4.9% ethanol-containing diet after DEN injection for 4 months	[58,59]
NAFLD	♦Inactivation of Wnt/β-catenin signaling resulting from inactivating mutations of LRP6 in mice leads to hyperlipidemia as well as fatty liver disease, validated by rescue using Wnt3A.	[63,64,65]
	♦Restoring of Wnt/β-catenin signaling in progression to NASH and HCC by the overexpressed ACLP, increased secretion of Wnt ligands from infiltrating macrophages, hypermethylation of Wnt antagonists, deacetylation of histones in AXIN2 promoter and downregulation of microRNAs negatively regulating Wnt/β-catenin signaling	[15,66,67,68]
Aflatoxin-B1	♦Decrease of β-catenin due to upregulation of miR-33a and miR-34a in HCC cell lines	[71,72]
	♦Increase of β-catenin at cell membrane in HCC tissues	[73]