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Page 6 of 11 Raza et al. Hepatoma Res 2019;5:42 I http://dx.doi.org/10.20517/2394-5079.2019.014

stress are known to stimulate nuclear factor kappa-light-chain-enhancer of activated B-cells pathway,
[94]
which promotes hepatocyte survival . ROS and the products of lipid peroxidation stimulate the release
[95]
of inflammatory cytokines including tumour necrosis factor-alpha (TNF-α) and IL-6 from hepatic cells .
[67]
TNF-α is reported to promote hepatocellular carcinogenesis by activating hepatic progenitor cells . IL-6
activates the signal transducer and activator of transcription 3, an oncogenic transcription factor that
induces cell proliferation, inhibits apoptotic pathways and may be involved in the development of NASH-
[96]
associated HCC [Figure 1]. Similarly, other cytokines such as IL-17A and IL-11 have also been implicated
in NASH and NASH-associated HCC [97-99] .

Cellular injury activates the hedgehog signalling pathway, which is involved in repair and regeneration in
the liver and replaces damaged hepatocyte. The Hedgehog signalling pathway is implicated in fibrogenic
[100]
activation and hepatocellular ballooning , features associated with the advancement of NASH. Impairment
of the Hedgehog pathway also leads to dysregulation of cell repair mechanisms and promotes the malignant
[101]
transformation involved in the progression of HCC . The TGF-β signalling also mediates the progression of
fibrogenesis through regulation of cell death and lipid metabolism in NASH [102,103] [Figure 1].

The role of CD8+ and CD4+ T lymphocytes in hepatocyte damage and carcinogenesis has been studied
[104]
in various animal models . In mouse models and human samples, dysregulation of lipid metabolism in
NAFLD causes a selective loss of intrahepatic CD4+ but not CD8+ T lymphocytes, leading to increased
inflammation and accelerated development of HCCs [105] . Platelet cargo, platelet adhesion and platelet
activation appear to be pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet
GPIbα is a mediator of hepatic immune cell trafficking and antiplatelet therapy (e.g., aspirin/clopidogrel
and ticagrelor) has been demonstrated to prevent NASH and subsequent HCC development [106] . One
recently published study used a new zebra fish model and reported that a high fat diet promotes non-
[107]
resolving inflammation in the liver and enhances cancer progression . The authors found that metformin
inhibits high fat diet-induced HCC progression, by reducing inflammation and restoring tumour
[107]
surveillance .

Endocrine pathways
Several hormones play important roles in the pathogenesis of NAFLD and its consequent progression to
HCC. One of the most crucial in these is insulin resistance and hyperinsulinemia, which is an associated
feature of NAFLD [108] . Insulin resistance and hyperinsulinemia are known to increase the expression of
insulin and insulin-like growth factor-1 (IGF-1). Insulin and IGF-1 trigger signalling cascades by binding
to their receptors, namely the insulin receptor and the IGF-1 receptor, to activate the PI3K and MAPK
pathways, which are crucial in the pathogenesis of HCC since they induce cell proliferation and inhibit
[109]
apoptosis . In particular, the PI3K pathway mediates the progression of HCC by cyclin D1-dependent
control of the cell cycle, mTOR dependent cellular growth and mouse double minute 2 homolog Mdm2/
p53-dependent apoptosis [110] . Interestingly, there can be cross-talk between other signalling pathways
and PI3K-mediated signalling; e.g., hippo signalling suppresses IRS2/Akt-mediated HCC development in
[111]
rodent models . Activation of the MAPK pathway by insulin resistance induces the expression of proto-
oncogenes, c-fos, and c-jun, and promotes hepatic fibrosis and carcinogenesis by activating the Wnt/
[112]
β-catenin signalling cascade [Figure 1].
NAFLD is also associated with increased circulating levels of leptin [113] . Leptin initiates intracellular
signalling of pro-inflammatory cytokines such as TNF-α and IL-6 and activates JAK2/STAT, MAPK and
[114]
PI3K signalling pathways by binding to its receptor in HCC cells . Furthermore, leptins are known to
[115]
upregulate hTERT expression, leading to the immortalisation of HCC cells . NAFLD is also associated
with decreased sensitivity to thyroid hormones [116] and both NAFLD and HCC are associated with
hypothyroidism in humans [117,118] . Furthermore, thyroid hormone treatment decreases hepatosteatosis and