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Page 4 of 15 Song et al. Hepatoma Res 2020;6:27 I http://dx.doi.org/10.20517/2394-5079.2020.05

HBV DNA integration
HBV DNA integration occurs early once HBV entering into hepatocytes and remains stable throughout
tumor progression, which explains the existence of monoclonal or polyclonal origins of HCC from the
view of virus infection [45,46] . HBV DNA susceptibly integrates into rare fragile sites or functional genomic
regions, which are proximate to protein coding or non-coding genes. Functionally, the protein-coding genes
are deeply associated with tumorigenesis and the non-coding genes are involved in telomere maintenance,
protein modification processes, and chromosome localization [47-49] . For example, integration drives mutation
in tumor suppressor gene ZNF717 and over-expression of critical oncogene c-MYC. Meanwhile, integration
into intron of cyclin A2 generates a pseudo-exon forming a chimeric fusion with CCNA2, which encodes
protein promoting cell cycle progression [46,50,51] . Moreover, HBV DNA integration is closely correlated with
gender-bias and recurrence of HCC. Androgen receptor, but not estrogen receptor, enhances transcription
responsive of TERT promoter with HBV integration to sex hormones via hepatocyte nuclear factor 4 alpha
[52]
(HNF4α)- dependent manner . Multiple studies have identified fragile integration sites more in non-
cancerous tissue than those in neoplastic tissues, which implies tumor recurrence [48,53] .

Genomic instability
In infected hepatocytes, both HBV DNA integration and viral proteins lead to genomic instability.
Sequencing analysis of 373 liver cancer samples demonstrated ultra-high structural instability and preserved
[54]
un-methylation in HBV integrated regions . HBx directly induces genomic instability via inhibiting mono-
ubiquitylation of an evolutionarily conserved E3 ligase and impairing homologous recombination, which
[55]
contribute to tumorigenesis . LHBs are the major viral protein leading to genomic instability. By inducing
DNA damage and G2/M checkpoint failure, LHBs promote formation of hepatocyte aneuploidy and further
self-propagating cycles of chromosomal instability, which drives cellular heterogeneity and clonal cancer
evolution [56,57] .

NAFLD
NAFLD and its complication nonalcoholic steatohepatitis (NASH) are becoming the leading cause of
HCC. Multiple pathways, such as abnormal metabolism, dysbiosis of gut microbiota and dysregulated
immune responses, are involved in NAFLD initiated hepatocarcinogenesis and have been well summarized
[58]
recently . Here, we mainly focus on dysregulated pathway mediated by lipid accumulation which is
fundamental in progression of NAFLD related HCC. The abnormal intrahepatic lipid metabolism invokes
insulin resistance, alteration of signaling pathways and oncogenes, followed by inflammation, fibrogenesis
and hepatocarcinogenesis. In clinical samples, level of p-STAT5 is positively correlated with expression of
sterol regulatory element binding protein-1 (SREBP1) and further in vivo and in vitro essays demonstrate
that mTORC1 interacts and phosphorylates STAT5 to upregulate expression of lipogenetic genes, including
[59]
SREBP1, fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC) . Both oxidative and ER stress
caused by chronic lipotoxicity play critical roles in NAFLD-HCC. Oxidized LDL (oxLDL) uptake triggers
CEBPβ expression to directly upregulate Nogo-B, an ER-residential protein, and promote lipophagy leading
[60]
to lysophosphatidic acid-enhanced YAP oncogenic activity . In addition to hippo signaling pathway,
STAT3-mediated pathways are frequently involving in pathogenesis of NAFLD-HCC, which mediated lipid
accumulation, apoptosis and fibrogenesis [61-66] .

Other than metabolic disorder, gene polymorphism is significantly responsible for NAFLD. Recent genome-
wide association studies (GWASs) in European ancestry suggest a robust relationship of PNPLA3 gene cluster
with NAFLD activity, progression to HCC and liver-associated death [67-69] . This study also demonstrated
[67]
an association of novel loci near IL17RA and ZFP90-CDH1 with NAFLD disease severity and fibrosis .
rs368234815 variant in IFNL4 and FNDC5 rs3480 polymorphism are respectively identified to be associated
with liver damage and fibrosis in patients with NAFLD [70,71] . In addition, gender-bias is as well observed in
NAFLD-HCC. As the confirmed risk factor for male HCC, androgen receptor (AR) transcription activity is
enhanced by key enzymes and specific unsaturated fatty acid produced in lipogenesis via activation of Akt
[72]
kinase [Figure 1].