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Sukowati et al. Hepatoma Res 2019;5:2 I http://dx.doi.org/10.20517/2394-5079.2018.106 Page 5 of 9

isolated tumor-initiating stem-like cells (TISCs) with the phenotype of CD133+ CD49f+ showed that TISCs
[39]
expressed higher levels of stemness genes and Twist1 .

It was known that HCV core protein induces the upregulation of transforming growth factor beta 1 (TGFβ1),
[40]
showing a direct role in fibrogenesis . A recent study on HCV core protein demonstrated that the TISCs
obtained from the model had the capacity to recruit and activate fibroblasts in a xenograft, exhibited
by high expression of fibrogenesis and EMT markers. It showed that in HCV infection, preneoplastic or
[41]
tumorigenic state of the hepatocytes influenced the network for the tumor environment , presumably
with the involvement of the hepatic cells stemness. As seen in NS5A transgenic mouse, a study in HCV
core transgenic mouse with HCV core insertion showed a corresponding result. The TISCs isolated from
this mouse were tumorigenic both in vitro and in vivo and the TLR4-Nanog pathway was necessary for the
[42]
maintenance of tumorigenic properties .
The Wnt/β-catenin pathway might be the major or one of the major molecular mechanisms involved in the
oncogenicity of HCV. The activation of this pathway was noted in transgenic expressions of both HCV core
and NS5A proteins. Pharmacological inhibition or loss of the Wnt/β-catenin signal represses TISCs growth
[43]
in vitro, and decreases the accumulation of TISCs in vivo .
Regarding the core protein, since HCV core is closely related with TGF-β pathway, it is expected that TGF-β
is involved in the induced CSC population. A previous study showed that CSC generation by HCV core protein
was dependent on the endoglin (CD105), a TGF-β receptor complex. Besides the increase of CSC proteins anti-
[44]
apoptosis and proliferation are enhanced during infection or ectopic expression of HCV core .
As in HBV, epigenetic mechanisms such as DNA methylation could give a hint on the molecular mechanism
of the oncogenicity HCV. It was shown that demethylation of CpGs induced Sal-like protein 4, an embryonic
stem cell transcriptional regulator. This re-expression was noticed in subgroups of HCC associated with
[45]
HBV or HCV infection .

RELEVANCE OF CSC MARKERS IN CLINICOPATHOLOGICAL FEATURE OF HCC
The complexity of HCC showed that the heterogeneity is not limited among patients (intertumoral
heterogeneity) but also within the same person (intratumoral heterogeneity). Cell morphology, molecular
[46]
profile, and expression of specific markers can be used to stratify and classify discrete tumor subtypes .
Consequently, HBV and/or HCV infection contributes to phenotypic and molecular characteristics in
hepatic cell populations, including the CSC.

Multiple clinical studies had shown that the high expression of CSC marker CD133 in HCC tissues, in
particular in the cytoplasm, is correlated with a poor prognosis [47-51] . In addition to prognosis, CD90 is high-
[52]
expressed in HCC nodule and is correlated with HCC differentiation grades [53,54] .

Protein analysis showed that the levels of hepatic CD133 were higher in HBV+ than those in HBV- HCC
[22]
tissues , pointing to the oncogenicity of the PreS1. Recent data showed that in HBV-related HCC cases,
CD133 in combination with the level of serum AFP, HCC could be subclassified into four subtypes, with
different clinicopathological features and various prognosis. A high expressions of both CD133 and serum
[55]
AFP was associated with a relatively poor prognosis .

However, a previous study in endemic HBV area showed that CD133 expression in HCC was negatively
[56]
associated with the presence of HBsAg . A histological analysis of human tissue found a positive
[57]
correlation between HBV and CD90 but since co-staining of the CSC markers and the HBV proteins was
not performed, it remains unclear if and how HBV alters the physiology of CD90+ and CD133+ CSC.