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Yoon. Hepatoma Res 2018;4:42 I http://dx.doi.org/10.20517/2394-5079.2018.23 Page 3 of 9

[13]
its target genes ; and (4) regulation of cellular signaling pathways, such as activation of the Ras-Raf-MAPK
pathway, Src-dependent pathway, PI3K-Akt pathway, inflammation-associated NF-kB/STAT-3 pathways, and
wnt/β-catenin pathway [14-18] . In addition, HBx affects epigenetic alterations through hyper- or hypomethyl-
ation of oncogenes and tumor suppressor genes, promoting histone acetylation and de-acetylation of tumor
related genes as well as alterations of several microRNAs [19-21] .

MOLECULAR MECHANISMS OF HCV-RELATED HCC
HCV is a single stranded RNA virus with a 9.6-kb genome that encodes a large polyprotein that is cleaved
at multiple sites to produce at least 10 proteins, including structural proteins [core, envelope (E)1 and E2]
and non-structural (NS) proteins (proteins p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B). Epidemiologic
studies worldwide have provided evidence that HCV is the major risk factor of HCC, and that chronic HCV
infection induces liver fibrosis and cirrhosis, ultimately resulting in HCC. Historically, after identification
of HCV, it has been very difficult to study its pathogenesis and development into chronic liver diseases and
HCC due to the lack of in vitro culture systems. To overcome this limitation, transgenic animal models ex-
[22]
pressing single or multiple HCV viral proteins were developed . Despite these models, evidence for HCV
[23]
playing a direct role in hepatocarcinogenesis remains controversial . Because of revolutionary studies on
viral replication in cell culture [24,25] , studies investigating hepatocarcinogenesis by HCV have been actively
performed. HCV that replicates only in the cytoplasm of a hepatocyte has not yet integrated into the host
genome. Integration of viral elements into the host genome leads to direct oncogenic transformation of
hepatocytes. Several studies have provided evidence for a direct role of HCV in the pathogenesis of HCC.
Previous studies have described the role of the HCV core protein related to the development of HCC. The
[27]
[26]
HCV core protein activates STAT3 via an IL-6 autocrine pathway and enhances telomerases activity ,
which can induce oncogenic transformational changes in hepatocytes. In addition, NS3/4A enhances cellular
proliferation by activating phosphorylation of extracellular signal-regulated kinases (ERKs) and inhibiting
p53-mediated apoptosis and p21 promoter activity [28,29] . In addition, chronic HCV infection induces onco-
[30]
genic transformation in several ways: vigorous and continuous inflammation via NF-kB ; oxidative stress,
[31]
[32]
inducing DNA mutagenesis ; alteration of tumor suppressor genes ; direct alteration of the wnt/β-catenin
pathway by NS5A; and blocking of TGF-β signaling through an interaction between TGF-β receptor I (TβR-I)
[33]
and NS5A . Moreover, a recent study demonstrated that a lack of microRNA-122 resulted in a high inci-
[34]
dence of tumors in a mouse model, but the mechanism by which this occurs has not been elucidated .
Patients coinfected with HBV and hepatitis delta virus (HDV) have been reported to have rapid and serious
[35]
disease progression . However, little is known about whether and how co-infection of HBV and HDV can
accelerate hepatocarcinogenesis. Recent studies suggest that marked liver inflammation, dysregulation of
nuclear signaling pathways, increased oxidative stress, and epigenetic changes through HDV replication can
[36]
enhance malignant transformation of hepatocytes, resulting in accelerated HCC development .

MOLECULAR MECHANISMS OF ALCOHOL-RELATED HCC
Alcohol consumption, particularly over-consumption, is a serious global health problem. In general, heavy
alcohol consumption leads to fatty liver, alcoholic steatohepatitis (ASH), cirrhosis, and eventually, HCC.
[37]
ASH has been reported to progress to HCC at a rate of 3%-10% annually . Though the pathogenetic mecha-
nisms underlying alcohol-induced tumor initiation have been well defined, the alcohol-related signaling
pathways involved in tumor promotion and progression are poorly understood.

Induction of Cytochrome p450 2E1 (CYP2E1), a member of the cytochrome p450 mixed-function oxidase
system, by chronic alcohol consumption induces various biologic effects, such as increases in alcohol metab-
olism, enhanced oxidative stress, increased hepatotoxicity and interactions with various drugs, xenobiotics
[38]
and carcinogens . In particular, acetaldehyde produced by alcohol metabolism strongly induces oxidative