Page 30 - Read Online

Page 6 of 9 Sukowati et al. Hepatoma Res 2019;5:2 I http://dx.doi.org/10.20517/2394-5079.2018.106

Recent data also showed a correlation between HBV and CSC EpCAM. High expression of HBx in human
HBV-related HCC was also correlated with the expansion of EpCAM HCC cells; EpCAM expression was
detected more frequently with HBV than with other etiologies. Further, in chemotherapy treated patients,
[24]
EpCAM was strongly expressed, indicating its association with treatment resistance .
In contrast to the clear direct oncogenicity of HBV, the association between clinical and pathological
characteristics and CSC markers in HCV-related HCC is still very limited. Recently it was demonstrated
that CSC spheres induced by HCV were highly sensitive to cell death from sorafenib. It can be a basis for the
development of new targeted therapies against hepatic CSC [35,58] .

PERSPECTIVES
While the pathogenesis of HBV and HCV proteins in the development of HCC has been intensely
investigated, information on their significance in the initiation of hepatic CSC is still very limited. It is
because the theory of CSC in HCC is still relatively new and further evidence must be demonstrated.
Moreover, even though this hypothesis is exciting, CSC theory in HCC is debatable and controversial.
Recent studies had indicated that in gastrointestinal cancers, the so-called CSC should be defined as tumor-
initiating cells/TISCs. These cells were not pluripotent, but bi- or multipotential to give rise to diverse tumor
[59]
types and tumor initiation potential in mouse models . The complexity of the liver, as well as the limitation
in the experimental models, still limit the proof of the CSC concept. Further, genomic diversity and genetic
characteristic of the virus (genotypes, subgenotypes, and quasispecies) significantly contribute to different
[33]
clinical outcome and viral susceptibilities .

In addition to the type of the virus, another point to be considered is the state of the hepatic cells during viral
exposure. A recent study had shown that the susceptibility of the hepatic cells to HCV was different during
cellular maturation course. In this study, an epigenetic transduction by pluripotency factors reprogrammed
mature cells into hepatic oval (progenitor) cells. In this progeny stage, cells lost their susceptibility to HCV
infection and viral RNA replication. Upon hepatic differentiation, however, a permissiveness to HCV RNA
replication was re-obtained. In contrast to HCV, in HBV infection, viral susceptibility was maintained along
the course. It indicated that during hepatic maturation process, cells receptor susceptibility are specific to
[60]
particular virus .

Even though basic in vitro studies and studies in transgenic animals, as well as clinical data from HCC
patients, had shown expanded evidence on “stemness” oncogenicity of HBV and HCV, the mechanism
of how viral particle induces hepatocarcinogenesis is still unclear and open for discussion. We presume
that there would not be a single answer because of the complexity and heterogeneity of both virus and
host factors. Finding strong evidence on this field will keep us busy for some time but the application of
potentiality of this trip is intriguing.

DECLARATIONS
Authors’ contributions
Designed the manuscript: Sukowati CHC, Tiribelli C
Wrote, read and approved the manuscript: Sukowati CHC, Reyes PAC, Tell G, Tiribelli C

Availability of data and materials
Not applicable.

Financial support and sponsorship
Sukowati CHC was supported by a Research Grant of Associazione Italiana per la Ricerca sul Cancro (AIRC