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Page 4 of 11 Raza et al. Hepatoma Res 2019;5:42 I http://dx.doi.org/10.20517/2394-5079.2019.014

[46]
member 2 gene (TM6SF2) mutations are also prevalent in NASH patients . They are believed to be linked
[47]
to liver injury in the pathogenesis of NASH-associated HCC . Recently, membrane bound O-acetyl
transferase domain containing 7 (MBOAT7) rs641738 variant associated with NAFLD progression has also
[48]
been linked to HCC susceptibility [Figure 1].
In addition to the SNPs, genetic instability is also believed to stimulate the progression of NASH to HCC.
Mutations in oncogenic genes, such as the human telomerase reverse transcriptase (hTERT) gene which
catalyses the addition of nucleotides to the ends of eukaryotic chromosomes, tumour protein p53, cyclin
dependent kinase inhibitor 2 A, albumin, catenin beta-1 and axis inhibition protein 1 (involved in Wnt/
[49]
β-catenin signalling), are prevalent in exome-sequencing analysis of HCC . Aberrant DNA methylation is
[50]
also an important mechanism in NASH progression , and can lead to silencing of genes involved in DNA
[50]
repair, lipid metabolism, glucose metabolism and progression of fibrosis . In particular, the epigenetic
changes in the gene encoding chromodomain helicase DNA-binding protein 1 are reported to be linked to
[51]
NASH-associated HCC .
The expression of several microRNAs (miRNAs) also is reported to be dysregulated in many types of
[52]
cancer, including NASH-associated HCC . The miRNAs are small noncoding RNAs that down-regulate
gene expression by interfering with transcription and/or translation. These miRNAs are involved in cell
signalling pathways associated with oncogenesis, such as transforming growth factor (TGF)-β, Wnt/
β-catenin, mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinases (PI3K)/AKT/
[53]
mTOR pathways, which can be activated in HCC . In particular, miRNAs known to target the inhibitors
of PI3K/AKT pathway are found in HCC. In this connection, steatosis, hepatomegaly and HCC have been
[54]
observed in phosphatase and tensin-deficient mice . Several miRNAs are differentially expressed in a
[55]
high fat diet mouse model during the NAFLD-NASH-HCC transitions . Hepatic miR-340-5p, miR-484,
miR-574-3p and miR-720 were expressed in NAFLD, NASH and HCC, and miR-125a-5p and miR-182
[55]
showed early and significant dysregulation during hepatic tissue damage .
Metabolic pathways
The association of obesity, high-fat diet and diabetes to NAFLD/NASH and its progression to HCC suggests
the existence of a molecular link between energy metabolism and cell cycle control in the hepatocytes,
which may be a key mechanism driving the progression of NASH to HCC. Several animal studies have
been conducted to investigate NASH-associated HCC. These studies showed that the progression of NASH-
associated HCC may be due to abnormal lipid metabolism, oxidative stress, ER stress and mitochondrial
dysfunction acting independently or in tandem [56,57] [Figure 1].

It is worth noting that mitochondrial activities such as β-oxidation, electron transfer, ATP production
[58]
and ROS generation regulate the fat metabolism and energy homeostasis in hepatocytes . During the
early hepatosteatoic phase of NAFLD when there is fatty acid accumulation in hepatic cells, mitochondria
prevent oxidative stress and help facilitate the partition of lipotoxic FFAs into stable triglycerides that can
[59]
be stored in fat droplet, and thereby prevent oxidative stress . However, chronic high-fat or high-fructose
diet leads to lipid over-accumulation in the hepatocytes due to cellular metabolic reprogramming and
[60]
accumulation of toxic metabolites . These changes lead to imbalances in hepatic metabolism that result in
[61]
excessive production of FFAs, which can cause lipotoxicity .
The excessive accumulation of these fatty acids increases β-oxidation and ROS production, which
[62]
can limit mitochondrial function . When these mitochondrial abnormalities are accompanied by
[63]
diminished intracellular antioxidant protection in NASH, pathways of fatty acid metabolism are altered ,
[63]
which, in turn, can cause metabolic stress . Overproduction of ROS frequently occurs in cancer,
[64]
and is believed to play an important role in the development of HCC . Intriguingly, oxidative stress