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Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38 Page 7 of 22

alteration of the structure of the hepatic parenchyma. The increase in hepatocyte turnover due to the
continuous processes of cell death and regeneration, as well as the progression of fibrosis, lead to a high
probability of genetic alterations, whose accumulation leads to the formation and proliferation of cell clones
[85]
that favour the development of HCC . Furthermore, apoptosis of hepatocytes can amplify the fibrogenic
signal, thus stimulating the activation of stellate cells and causing the progression of hepatic fibrosis towards
[86]
cirrhosis which is a pre-malignant condition . HCV infection is also able to modify the intracellular
signalling pathways of transforming growth factor beta (TGF-β) signalling, thus accelerating the progression
[87]
of liver injury and increasing the risk of HCC .

Although the pathogenesis of HCV-related HCC is mostly due to the development of cirrhosis and cell
regeneration mechanisms, different alterations in gene expression and signal transduction pathways involved
in cell proliferation and in the neoplastic transformation of hepatocytes have been described in chronic HCV
[88]
infection . In this regard, there are various demonstrations, mostly obtained on animal models, which
suggest that different viral proteins may play a direct role in hepatocarcinogenesis [85,89-92] . The NS3 non-
structural protein is a serine protease that appears to be involved in the neoplastic transformation process by
inducing the acquisition by the hepatocyte clones of a proliferative condition, as well as the escape from the
[89]
host cell surveillance mechanisms . In combination with the NS4A factor, it interacts with the ATM kinase
[93]
and alters DNA cell repair mechanisms . Similarly, the NS5A phosphoprotein appears to be able to alter
the cell growth mechanisms and the physiological replication cycle of the host cell through interaction with
[90]
the CDK1/2-cyclin kinase-dependent complex . The HCV core protein and the E2 envelope protein have
been shown to stimulate cell growth and heteroplastic degeneration [91,92] . The HCV core protein in particular
seems to play a key role in the pathogenesis of HCC. Its oncogenic potential appears to be considerably high,
as it causes oxidative stress on one side and alters the intracellular signalling cascade of the protein kinase
[85]
on the other, resulting in a dysregulation of cell growth control . In particular, the HCV core-protein
is able to provoke an overproduction of ROS by increasing the lipid peroxidation and a mitochondrial
dysfunction through the rearrangement of the lipoprotein double layer of the mitochondrial membrane [94,95] .
The oxidative stress induced by the HCV core-protein leads to damages in the genome of the host cell with
accumulation of genetic aberrations that predispose the evolution towards cancer [85,95,96] . Furthermore, the
presence of insulin resistance and hepatic steatosis, which are associated with a high frequency to HCV
[95]
infection, exacerbates the production of ROS . In addition, the HCV core-protein is able to inhibit DNA
repair mechanisms damaged by oxidative stress and alter various intracellular antioxidant systems [95,97] . At
the same time, this protein is able to directly alter gene expression and intracellular regulation mechanisms.
In this regard, a greater expression of tumor necrosis factor-a (TNF-a) and interleukin-1β (IL-1β) was
observed, together with an higher activity of the relative downstream effectors c-Jun N-terminal kinase and
activator protein-1, and a stimulation in the mitogen-activated protein kinase (MAPK) cascade [98,99] . HCV
core-protein is also capable of inhibiting the tumor suppression genes RB1, TP53 and TP73 as well as cell-
cycle modulators such as CDKN1A [98,100] . Cytokinesis overexpression and gene expression alterations may
represent the mechanisms through which HCV core-proteins modulate the apoptotic signalling pathways
and mechanisms of defence and proliferation of the hepatocytes. Histologically, transgenic mice carrying
the core gene develop an early hepatic steatosis, similarly to what happens in men during chronic HCV
infection. These mice show progressively the onset of hepatocellular adenomas characterised by the presence
of numerous intracytoplasmic fat drops, which then evolve towards the formation of HCC more or less rich
[101]
in lipid drops, depending on the stage of differentiation . These data highlight the key role played by HCV
core-protein in the process of carcinogenesis.

HCV is able to cause alterations in the glucose and lipid metabolism, another important factor in the
[85]
development of HCC . HCV, in fact, stimulates the activation of insulin-like growth factor (IGF), a cell
[102]
growth regulator, through the induction of proliferative and anti-apoptotic mechanisms . Through the
[103]
degradation of insulin receptor substrate 1 and 2 (IRS-1 and IRS-2) , the virus is also able to interfere with