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

stress, exacerbating liver diseases.

Recent studies have described the association between CYP2E1 polymorphisms and alcohol-related disor-
ders, including alcoholic cirrhosis [39,40] , but no significant association was found between CYP2E1 Pst I/Rsa
[41]
I polymorphism and HCC in a recent meta-analysis . The molecular mechanisms for the direct role of al-
cohol on hepatocarcinogenesis remain unclear. However, a recent large-scale study using exome sequencing
analysis of 243 liver tumors identified mutational signatures associated with specific risk factors and dem-
onstrated that the Catenin beta 1 (CTNNB1) cluster was significantly related to alcohol as a risk factor for
[42]
HCC .

Sirtuins (SIRT1), nicotinamide adenine dinucleotide+ (NAD+)-dependent class III histone deacetylases, are
[43]
linked to histone deacetylation and suppression of gene transcription, as well as the aging process . A pre-
vious study illustrated that alcohol reduced hepatic SIRT1 expression, suggesting that loss of SIRT1 activity
[44]
may initiate alcoholic liver disease . However, the role of SIRT1 in the development and progression of tu-
mors remains controversial. Numerous studies have demonstrated that SIRT1 acts to inhibit cell transforma-
tion and tumor progression, but other studies have suggested tumor promoting roles for SIRT1 [45-47] . In the
[48]
context of HCC, a recent study by Jang et al. demonstrated the existence of positive feedback regulation
between c-myc and SIRT1 that promotes tumor cell proliferation and predicts poor survival in human HCC.
[49]
More recently, Mercer et al. performed in vivo experiments using ethanol feeding for long periods follow-
ing injection of diethylnitrosamine (DEN). Their results suggest that chronic ethanol consumption activates
Wnt/β-catenin signaling, leading to increased hepatocyte proliferation and promotion of tumorigenesis fol-
lowing an initiating insult to the liver.

MOLECULAR MECHANISM OF NASH-RELATED HCC
NAFLD comprises a spectrum of liver disorders from simple fatty liver to NASH, hepatic fibrosis/cirrho-
[50]
sis and HCC. Individuals with NASH progress to HCC at a rate of 0.5% annually . The risk factors for
NAFLD include metabolic syndrome, visceral adiposity, extreme dieting and type 2 diabetes. Additional
factors accelerating the transition from simple fatty liver (SFL) towards NASH and HCC include the gut
[51]
microbiota, adipose-related inflammation, and excessive intake of lipids . NASH associated with end-stage
[52]
liver disease (ESLD) and HCC have become the second leading causes of liver transplantation in the USA .
Generally, SFL is reversible through weight control by exercise and calorie restriction. However, once SFL
has progressed to NASH, medical attention is required because of its progression to ESLD or HCC. To date,
numerous animal models have been established to investigate NASH-associated HCC, but these models have
limitations for elucidating cause-and-effect relationships in the development of HCC. Nonetheless, these
animal models have provided crucial evidence for pathogenic mechanisms in NASH-associated HCC. The
process of liver injury occurs through activation of oxidative stress, endoplasmic reticulum (ER) stress, mi-
[53]
tochondrial dysfunction, autophagy and intrahepatic NKT and CD8+ T cells . During the inflammatory
process in NASH, several cytokines, adipokines and lymphokines contribute to hepatic fibrogenesis via the
[54]
regenerative process of hepatocytes . In addition, recent studies have demonstrated that up-regulation of
[55]
the insulin-like growth factor 1 (IGF1)/insulin substrate 1 pathway by hyperinsulinemia and enhancement
[57]
[56]
of IL-6 and TNF levels by obesity contribute to hepatocarcinogenesis. Interestingly, a study by Yoshimoto et al.
suggested that obesity-induced gut microbial metabolites promote liver cancer through the senescence sec-
retome. In summary, the hepatic microenvironment of NASH, which is considered to be a proinflammatory
milieu, plays an important role in the development and progression of HCC.

Genetic factors as well as environmental factors have also been considered to be risk factors for NAFLD-
associated HCC. The nucleotide polymorphisms rs738409 C/G, which results in an isoleucine to methionine
substitution at residue 148 (I148M) in human patatinlike phospholipase domain containing 3, leads to an
alteration of TAG remodeling in lipid droplets. This variant has been linked to an increased risk for liver