Page 141 - Read Online

Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38 Page 5 of 22

proteins mutated at the endoplasmic reticulum may be able to induce the formation of ROS, with consequent
oxidative stress to the host DNA and induction of the hepatocyte transformation [12,43-45] . Mutations in the S
region can also contribute to the development of HCC. In this regard, it has recently been shown that a non-
sense mutation at position 172 or 182 of viral genome can contribute significantly to the progression of liver
[46]
disease, and in particular the sW182 mutation was found to be related to the development of HCC .

In addition to the structural proteins, the viral genome also codes for HBx proteins that is involved in the
transcription mechanisms of cccDNA and viral replication and seems closely related to the oncogenicity
of HBV [35,47,48] . HBx appears to be able to cause chromosomal instability affecting the mitotic checkpoints,
cell proliferation through stimulation of CREB genes, inhibition of apoptosis through interaction with
p53, promotion of neoangiogenesis through stimulation of vascular endothelial growth factor and angiopoietin
2 (ANG2) and induction of cell migration phenomena inducing the matrix metalloproteinase 3 and 9
expression [49,50] . Accordingly, HBx appears to be a crucial point of the oncogenic power of the virus, as well
[35]
as in promoting invasiveness and the ability to metastasize of HCC . HBx, among other things, inhibits
[51]
senescence mechanisms through inhibition of p53 and inactivation of the suppression factors of cancer .

A great research interest is growing on the effects of viral protein expression such as wild type and HBx
mutant, envelope and core proteins on different transcription and signaling pathways such as Wnt/β-catenin,
TGF-β, NFkB, Raf/MAPK, P53 and ROS involved in the pathogenesis of HCC related to HBV. The beta-
catenin pathway regulates multiple cellular processes and plays an important role in hepatocarcinogenesis
[52]
and in progression from chronic inflammation to HCC . Mutations in the CTNNB1 gene (catenin beta 1)
may activate the Wnt/β-catenin pathway and lead to the accumulation of β-catenin in HCC. The Wnt/β-
[53]
catenin pathway is a potential promising target for future molecular HCC therapies .
Effect of Immune-tolerance phase of HBV infection and occult HBV on development of HCC
The immune tolerance phase of HBV infection is characterized by a high level of viral replication in
the absence of significant cytolytic activity. These patients have been defined to be at low risk of disease
progression, so, at present, there is no indication for antiviral treatment [54,55] . However, recent studies have
questioned this principle by demonstrating high levels of chromosomal integration and clonal expansion
of the viral genome and hepatocytes, emphasizing that carcinogenesis may also occur at this stage and in
[56]
the absence of cytolytic activity . In addition, a prospective study showed that the estimated cumulative
incidence of HCC over a 10-year follow-up period is significantly higher in the immune tolerant group
[57]
than the active immune group (12.7% vs. 6.1%, respectively) . Furthermore, data from a recent study have
demonstrated the benefits in terms of clinical outcomes such as the development of cirrhosis and HCC of
[58]
antiviral treatment even during the immune tolerance phase . Therefore, it was hypothesized that HBV
[57]
positive patients not treated in the immune tolerance phase may be at a higher long-term risk of HCC .
On this basis it was suggested that the immune tolerance phase should not be more considered a “benign”
condition and that the levels of HBV-DNA rather than alanine aminotransferase (ALT) values should be
considered when estimating the risk of occurrence of HCC [58,59] . Further study and consensus will be needed
to define this important aspect.

A special mention must be made for the so-called occult HBV infection (OBI), a condition in which HBV-
DNA is detectable in the liver and possibly in the serum at low levels in the absence of HBsAg in the serum.
Several studies point out that the OBI can be a hazardous condition for the development of HCC [60,61] . In
these patients many of the above-described oncogenic mechanisms associated with HBV remain active.
Recent evidence has shown that an OBI condition was present in 75% of HBsAg negative HCC cases,
[62]
underlining the possible OBI role in HCC genesis . Furthermore, a condition of occult infection that
increases the risk of developing HCC seems to persist longer in the neoplastic tissue itself than in adjacent
tissue [61,63] . It has also been shown that the risk of developing HCC is significantly higher in patients with