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Page 8 of 18 Alqahtani et al. Hepatoma Res 2020;6:58 I http://dx.doi.org/10.20517/2394-5079.2020.49
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41-80 g and more than 80 g per day, respectively . Interestingly, studies have indicated that the synergistic
effect of alcohol on the HCC risk in HCV patients is not restricted to heavy drinkers and that even light to
modest alcohol use can promote the development of cirrhosis (and subsequent HCC) in HCV patients [100] .
In line with this, a study including 192 HCV patients with compensated cirrhosis, reported a 5-year
cumulative HCC rate of 10.6% among abstainers as compared to 23.8% among HCV patients with a light to
moderate alcohol consumption (median intake: 15 g/day) [101] .

HCV also comes with an increased risk of HCC in patients with DM. A meta-analysis evaluating the
association between DM and HCC in chronic HCV patients indicated a 2- to 3-fold increased risk [102] .
Similarly, a population-based cohort study from Taiwan indicated that DM increases the risk of HCC in
HCV-infected patients (HR = 1.36, 95%CI: 1.16-1.68;) [103] . Finally, NAFLD is a prominent characteristic of
a chronic HCV infection. In patients with genotype 3 HCV, the presence of NAFLD is directly linked to
the viral load, and in this setting, the NAFLD is considered to be of viral origin [104] . In contrast, in patients
with other HCV genotypes, the NAFLD is linked to host factors such as obesity. Studies have consistently
identified (NAFLD-related) steatosis as an independent factor associated with fibrosis progression in HCV
patients [105-108] . As such, it is not surprising to see that several studies (both retrospective and prospective)
have demonstrated that steatosis in HCV patients is also strictly associated with the development of
HCC [109-113] . An interesting study in this respect demonstrated that American chronic HCV patients were
found to progress more rapidly to HCC than their counterparts in China, with underlying fatty liver disease
as the prominent factor fueling this difference [114] .

Several prediction models for HCC have been developed for patients with an HCV infection (e.g., HALT-C,
REVEAL-HCV, and SCORE HCC ), but the performances of these scores are suboptimal, and their use and
validity in clinical practice are limited [115-117] .

Carcinogenic mechanisms
In contrast to HBV, HCV is a single-stranded RNA virus with little potential to integrate its genetic
material into the host. Therefore, HCV must exhibit its tumorigenic potential less directly. The mechanisms
involved in this process mainly involve two parts: induction of chronic inflammation and the expression
of viral proteins. HCV-induced HCC development is a multistep process that involves the establishment of
chronic HCV infection, persistent chronic hepatic inflammation, progressive liver fibrogenesis, initiation of
neoplastic clones accompanied by irreversible somatic genetic/epigenetic alterations, and progression of the
malignant clones in a carcinogenic tissue microenvironment [118] .

Several proinflammatory cytokines, including TNF-α, IL-1, IL-23, IL-6, and lymphotoxins α and β have
been implicated in chronic liver inflammation and the development of HCC [119] . Specifically, for HCV-
mediated hepatocarcinogenesis, a high ratio of TNF-α/IL-10 levels has been observed in the sera of patients
with severe liver damage and HCC [120] . Apart from immunological disturbances, epigenetic processes
were found to be involved in the development of HCV-related HCC. Like HBV-related HCC, HCV also
seems to profoundly impact the expression of certain miRNAs [121] . Similar to HBV, miRNA-155 also plays
a role in the development of HCC in HCV-infected patients. miRNA-155 levels are markedly increased in
patients infected with HCV, and this overexpression was found to stimulate hepatocyte proliferation and
tumorigenesis by activating Wnt signaling [122] . Other epigenetic studies have suggested a prominent role for
noncoding RNAs in the development of HCV-related HCC [123,124] .

With respect to the role of HCV-related proteins in the development of liver cancer, the HCV core protein
[62]
and NS5A seem to be of interest . In 1996, the HCV core protein was found to induce a carcinogenic
phenotype in primary rat embryo through a RAS-mediated mechanism [125] . The HCV core protein was also
shown to activate the MAPK signaling pathway, upregulate Wnt/β-catenin signaling, suppress apoptosis