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Cao Cancer Evo-Dev

predict the occurrence of HCC in longitudinal studies, the HBV genome, particularly at the C terminus of HBx
especially cohort studies [33-37] . The frequency of HBV (Ct-HBx) [59] . Ct-HBx can enhance cell invasiveness and
preS deletion also increases consecutively from ASCs metastasis of HCC in a manner that is more potent than
to HCC and preS mutation is associated with a 3.77-fold that evoked by full-length HBx and often predict the poor
increased risk of HCC [32] . The predictive value of HBV postoperative prognosis and ineffectiveness of antiviral
preS deletion on the occurrence of HCC in patients prophylaxis for HCC recurrence [51,60] . These evidence
chronically infected with HBV has been confirmed indicates that some HBV X mutants and large S mutants
in a prospective study [54] . Recent deep sequencing can promote the development and progression of HCC.
analysis has demonstrated that the preS deletions
involving a specific fragment (nt2977-3013) in HBV Interaction of genetic predispositions
genotype C are significantly associated with HCC [55] . of immune or inflammatory molecules
These epidemiological evidences indicate that the HBV with the HBV mutations in HBV-induced
mutations including preS deletion, A1762T/G1764A, hepatocarcinogenesis
C1653T, and T1753V are the etiological factors of HBV- As described above, the HLA-II genetic polymorphisms
induced HCC. Experimentally, in vitro transfection are statistically associated with the outcomes of
with the HBx mutants with changes that correspond to exposureto HBV [18-27] . This genetic background may
A1762T/G1764A, T1753A, T1768A, or a combination predispose immune imbalance upon HBV infection.
of these (combo) showed that the combo mutant In our previous epidemiological studies, we found that
decreased levels of p21, increased cyclin E expression, the HLA-II genetic polymorphisms are statistically
and increased expression of S-phase kinase-associated associated with the generation of the liver diseases-
protein 2 (SKP2) in primary human hepatocytes and associated HBV mutations. The HLA-DP polymorphisms
HepG2 cells. The combo mutant accelerated p21 rs3077 (CT + TT vs. CC), rs3135021 (GA + AA vs. GG),
degradation and cell cycle progression in HepG2 cells. rs9277535 (GA + AA vs. GG), and rs2281388 (CC vs.
Thus, HBx mutants with changes that correspond to CT + TT) significantly decrease HBV persistence in
a combination of the core promoter mutations up- genotype B HBV-infected subjects; HLA-DP genotypes
regulate SKP2, which then down-regulates p21 via that promote HBV clearance are associated with a
ubiquitin-mediated proteasomal degradation. The core lower prevalence of HBV mutations increasing HCC
promoter mutations might increase the risk of HCC by risk (C1653T, T1674C/G, A1846T, G1896A, preS2
this pathway [56] . Transfection of full-length HBV genome mutations, and preS deletion in genotype C) and a
with the core promoter mutations in combination also higher prevalence of HBV mutations decreasing HCC
upregulated SKP2 expression via activating the E2F1 risk (G1652A, T1673C, T1674C, G1719T, G1730C,
transcription factor and in turn downregulate cell cycle and G1799C in genotype B and A1727T in genotype
inhibitors, thereby accelerating cellular proliferation [57] . C); furthermore, significant effects of HBV mutations
Mutations in the preS and S regions also notably on cirrhosis and HCC are selectively evident in
facilitate carcinogenesis. Transfection of Huh7 cells those with the HLA-DP genotypes that promote HBV
with the large S region with preS deletion has shown persistence [61] . Thus, the HLA-DP polymorphisms affect
that HCC-associated single-nucleotide variants (SNVs) genotype B HBV clearance, regulate immune selection
in the small surface region of HBV genome influence of viral mutations, and influence cirrhosis and HCC
carcinogenesis pathways, including endoplasmic risks contributed by the HBV mutations. In addition,
reticulum-stress and DNA repair systems [55] . The HLA-DQ genetic polymorphisms rs2856718 variant
HBV large envelope protein gene fragment (preS1/ genotypes are significantly associated with an increased
preS2/S), with F141L mutation in the preS2 region, can frequency of HBV A1726C mutation, a cirrhosis-risk,
significantly promote the proliferation of hepatocytes HCC-protective mutation, in genotype C; a rs9275319
by downregulating the p53 and p21 pathways and variant genotype (GG) is significantly associated with
upregulating the expression of cyclin-dependent kinase an increased frequency of preS1 start codon mutation,
4 and cyclin A. The colony-forming rates of hepatocytes an HCC-risk mutation, in genotype C. Thus, the HLA-
expressing F141L-large envelope protein are about DQ polymorphisms affect the risks of cirrhosis and
twice as high as those expressing the wild-type HBV HCC differently in chronic HBV-infected subjects,
large envelope protein [58] . Random integration of possibly via interacting with the HBV mutations [62] . As
HBV DNA into the host genome is present in HBV- NF-κB and STAT3 are two most important inflammatory
infected subjects. If the integration events endow the pathways [10,11] , their genetic predispositions affecting
hepatocytes with growth advantage, the integration the expression of both signaling pathways may play
might facilitate the development of HCC, therefore, roles in HBV-induced hepatocarcinogenesis. We have
have the opportunity of being recorded. HBV integration demonstrated that STAT3 SNP rs2293152 (GG vs. CC) is
is common in HBV-HCC, leading to the truncation of significantly associated with HCC risk compared with the

246 Hepatoma Research ¦ Volume 3 ¦ October 27, 2017