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Review
. 2022 Dec 20;15(1):23.
doi: 10.3390/cancers15010023.

Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies

Jorge Gutiérrez-Cuevas  1 , Silvia Lucano-Landeros  1 , Daniel López-Cifuentes  1 , Arturo Santos  2 , Juan Armendariz-Borunda  1   2
Affiliations
Review

Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies

Jorge Gutiérrez-Cuevas et al. Cancers (Basel). .

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.

Keywords: current therapeutic strategies; epidemiology; epigenetic alterations; genetic and risk factors; hepatocellular carcinoma; metabolic reprogramming; nonalcoholic steatohepatitis; pathogenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Main risk factors for NASH and HCC development. Obesity is associated with the development of metabolic syndrome, diabetes, NAFLD, NASH, and HCC, which may act synergistically to accelerate the onset and development of NASH-derived hepatocarcinogenesis.
Figure 2
Figure 2
Pathogenic processes implicated in the onset and development of NASH-related HCC. Hyperlipidemia and hyperglycemia caused by obesity, promote insulin resistance and hormones dysregulation, which are responsible to trigger oxidative stress, inflammation, mitochondrial dysfunction, as well as dysregulation of autophagy and immune function, leading to NASH and ultimately HCC. Abbreviations: CRP, C-reactive protein; ER, endoplasmic reticulum; HIF-1α, hypoxia-inducible factor 1 alpha; NKT, natural killer T; NOX4, nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase 4; ROS, reactive oxygen species; Tregs, regulatory T cells.
Figure 3
Figure 3
Dysregulation of metabolic pathways in NASH and HCC. There is an increase in the TCA cycle and lactate (HSCs) production in NASH, while β-oxidation, lipid esterification, and intrahepatic lipolysis are decreased, leading hepatic steatosis. The tumor cells express an increase of glycolysis with production of lactate (Warburg effect), elevated pentose phosphate pathway (nucleotide synthesis for multiplying tumor cells), FA synthesis and lipogenesis. The tumor cells also show reduced TCA cycle, β-oxidation and gluconeogenesis, indicating that metabolic reprograming plays a key role in hepatocarcinogenesis. Abbreviations: DNL, de novo lipogenesis; FA, fatty acid; HSCs, hepatic stellate cells; TCA, tricarboxylic acid.
Figure 4
Figure 4
Representative epigenetic modifications in NASH and HCC. DNMT1 is essential for maintaining DNA methylation and is upregulated in NASH. Several genes have their promoter methylated in NASH and HCC. Other histone and mark modifications are involved in HCC, which are necessary to sustain tumor growth. Abbreviations: APC, adenomatosis polyposis coli; CCL20, C-C motif chemokine ligand 20; CDKN2A, cyclin dependent kinase inhibitor 2A; DNMT1, DNA methyltransferase 1; EGFR, epidermal growth factor receptor; ESR1, estrogen receptor 1; IGF2, insulin-like growth factor 2; Gnmt; glycine N-methyltransferase; NQO1, NAD(P)H: quinone oxidoreductase 1; MOF, males absent on the first; PNPLA3, patatin-like phospholipase domain-containing protein 3; PPARG, peroxisome proliferator activated receptor gamma; PPARGC1A, peroxisome proliferator-activated receptor gamma coactivator-1-alpha; RASSF1, ras association domain family member 1; SMAD6, SMAD family member 6; USP22, ubiquitin-specific protease 22.
Figure 5
Figure 5
Different therapeutic strategies for NASH and HCC. Abbreviations: PUFAs, omega-3 polyunsaturated fatty acids.
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