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

proteins provoke activation of the Wnt/β-catenin signaling pathway, and the evidence supporting a role of
Wnt/β-catenin signaling in the onset and progression of HCC is compelling [53,54] .

Progression of HCV-related liver diseases is noted to be accompanied by disturbances in β-catenin
overexpression, with its cytoplasmic or nuclear translocation and with lower expression of E-cadherin. More
β-catenin mutations are manifested in HCV-associated than in HBV-related HCC. HCV proteins affect
in a double manner expression of E-cadherin, including modulation of the Wnt pathway and reduction
of E-cadherin expression at the transcriptional level. Alterations in cellular locations of β-catenin and
E-cadherin in chronic HCV and HCC pointed to structural disturbances in intercellular junctions in livers
and presence of the transcriptionally inactive form of β-catenin [55,56] . Promoter hypermethylation of Wnt
inhibitors was discovered in HCV-induced multistep hepatocarcinogenesis , and the reduced expression of
[57]
E-cadherin in long-lasting chronic HCV might represent an early indicator of the epithelial-mesenchymal
transition [58,59] .

COUNTERACTIVE Wnt3a WITH Wnt5a IN HCC
Although accumulating clinical and basic evidences have suggested that the Wnt signaling is associated
with the HCC progression . However, little research has been reported on the relationship between Wnt3a
[60]
and HCC. Previous studies have found that Wnt3a showed higher expression in HCC than liver tissues,
positively correlated with its target genes MMP 7 and c Myc. Intriguingly, their expressions are significantly
correlated with Notch3 and Hes1 expression. Wnt3a was highly expressed in MHcc97H and SK Hep 1 cells
in vitro , as an important regulator of human HCC cell line growth, which could induce activation of the
[61]
canonical Wnt pathway after binding with SULF2 and GPC-3. Also, it could increase cell proliferation in
nude mouse xenografts in vivo [60,61] .

The expressions of hepatic Wnt3a were investigated in HCC tissues [Figure 1]. The positive Wnt3a with brown
staining particles was mainly distributed in cytosol and membrane of hepatocytes in cancerous tissues and no
or lower expression in their surrounding tissues. High Wnt3a expression like its down-stream disheveled 2,
DKK1, and SFRP1 were all identified as independent predictive factors for poor HCC outcome [20,62-64] . Compared
with high hepatic Wnt3a in HCC tissues, the significant difference of Wnt5a intensity was found between low
level in HCC tissues and high expression in their para-cancerous tissues. The intensity of Wnt5a expression was
inversely correlated with Wnt3a level in cancerous tissues. Both decreasing Wnt5a and increasing Wnt3a
expression in HCC tissues relation to the clinical staging from stage I to IV were confirmed as independent
prognosis factors of HCC patients. The Kaplan-Meier survival curves demonstrated that HCC patients with
high Wnt3a expression had a significantly lower survival rate compared to cases with lower Wnt3a [Figure 2],
Wnt3a expression was associated with poorly-differentiated grade, liver cirrhosis, chronic HBV infection,
and higher TNM stage, indicating that the abnormal Wnt3a expression could participate in promoting
hepatocytes malignant transformation and progression of HCC [65,66] .

SERUM Wnt3a FOR HCC SPECIFIC DIAGNOSIS
Early diagnosis of HCC is of the utmost importance. Successful screening for HCC at early stage is challenging
due to the lack of well characterized and specific biomarkers [67,68] . Data of previous studies have confirmed
that some Wnt signalings could modify HCC growth and invasive ability. However, achieving successful
screening of abnormal Wnt3a signaling is critically important as early diagnosis could potentially provide
an early monitoring opportunity. Along these lines, the Wnt pathway has been identified as contributing to
the development and progression of HCC. Although serological AFP marker is commonly applied to HCC
diagnosis, it has exhibited a low sensitivity and specificity with approximately 40% of negative patients.
Although many biomarkers have been applied in diagnosis for HCC, only a few markers were confirmed
with higher specificity or sensitivity for HCC, especially in early stage or small size HCC [69-71] .