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Yao et al. Hepatoma Res 2018;4:30 I http://dx.doi.org/10.20517/2394-5079.2018.32 Page 3 of 10

bonds. Analysis of the signaling activities of chimeric Wnt proteins has shown that the carboxy-terminal
region of Wnt proteins may play a role in determining the specificity of responses to different Wnts. The
amino-terminal region may mediate interactions with Wnt receptors but requires the carboxyl terminus to
activate these receptors. The main regulating mechanisms of Wnt signaling are either through canonical
pathway (Wnt1, Wnt2, Wnt3, Wnt3a, Wnt8a, Wnt8b, Wnt10a, and Wnt10b) characterized by the stabilization
and subsequent nuclear transport of β-catenin resulting in the activation of transcriptional responses or via
non-canonical pathway (Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, and Wnt11) with more diverse and
several different signaling modes that regulate cell biological behaviors [22-38] .

The Wnt signaling molecules have been involved in liver tumorigenesis with activating liver cancer stem
cells . In adults, Wnts function in homeostasis, and inappropriate activation of the Wnt pathway is
[39]
implicated in a variety of cancers. Some signaling molecules in the Wnt pathway have been recognized
to play an important role in the development and progression of tumors and regulate multiple cellular
events such as cell proliferation, differentiation, and apoptosis through β-catenin-dependent canonical- or
β-catenin-independent noncanonical pathway . Abnormal expression of some key molecules in the Wnt/β-
[40]
catenin pathway was associated with the development and progression of HCC. Wnt3a gene located on
chromosome (1q42.13) has been regarded as an activator inducing β-catenin accumulation and activating
the canonical Wnt signaling pathway. Studies on human Wnt3a have focused primarily on its key role in
liver malignancy, and its high expression in cancerous tissues has been confirmed with a worse outcome .
[20]

HBV INVOLVED IN Wnt ACTIVATION
HBV has a global distribution and is one of the leading causes of HCC. Its viral replication with several
pathways like Wnt/β-catenin, TGF-β, Raf/MAPK and ROS affects cellular persistence, multiplication,
migration, alteration and genomic instability [41,42] . The Wnt/FZD/β-catenin pathway associated with HBV-
related HCC development because of the progression of chronic liver diseases is known to be accompanied
by disturbances in β-catenin expression (mainly overexpression) [43,44] , with its cytoplasmic or nuclear
translocation. Viral proteins of HBV (HBx and HBsAg) can act as pathogenic factors that are involved in the
modulation and induction of canonical Wnt signaling activation with aberration of adenomatous polyposis
coli (APC), AXIN, secreted Frizzled related protein (SFRP) 1 and SFRP5.

The canonical Wnt signals are transduced through Frizzled receptors and LRP5/LRP6 co-receptors located
on the cell membrane, initiating the β-catenin signaling cascade [45,46] . This multi-protein destruction complex
could target the proto-oncogene β-catenin for ubiquitin-mediated proteolysis, prevent glycogen syntheses
kinase 3â (GSK-3â)-mediated β-catenin degradation, leading to nuclear translocation of β-catenin, combine
with T-cell factor/lymphoid enhancer factor, and thereby promote the transcription of downstream target
genes, including FGF20, DKK1, WISP1, MYC, CCND1, and so on. Their interaction results in the enhancement
of the pathway and leads to hepatocarcinogenesis [47,48] . Thus, lack of Wnt secretion from hepatocytes did not
affect overall injury, fibrosis or HCC burden although there were protein expression differences in tumor
conformation .
[49]

HCV PROVOKED Wnt SIGNALING
Epidemiological studies have validated the association between HCV infection and HCC. An increasing
number of studies show that protein-protein interactions between HCV proteins and host proteins play a vital
role in infection and mediate HCC progression . The role of nonstructural (NS5A) protein of HCV in vivo has
[50]
been accentuated in induction of this pathway mainly to the canonical pathway. Interaction of Wnt signaling
with HCV genome in hepatocarcinogenesis linked β-catenin phosphorylation and abnormalities in the
E-cadherin-catenin unit function lead to loss of intercellular junctions, progression in liver fibrosis, and
development of cirrhosis and HCC [51,52] . Accumulating evidence indicates that HCV core or nonstructural