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Page 2 of 8 Zheng et al. Hepatoma Res 2018;4:17 I http://dx.doi.org/10.20517/2394-5079.2018.08

explain the mechanisms of HBV related to tumorigenesis, including inflammation, liver regeneration
associated with cytotoxic immune injuries and transcriptional activators of mutant HBV gene products [7-10] .
The HBV genome consists of a circular, partly double-stranded DNA with four overlapping open reading
frames: (1) the pre-S/S open reading frame (ORF) encodes three viral surface proteins [including hepatitis
B surface antigen (HBsAg)/HBV surface (HBs)], (2) the pre-C/C ORF encodes the hepatitis B e antigen
(HBeAg) and the hepatitis B core antigen (HBcAg), (3) the P ORF encodes the terminal protein (TP) and the
viral polymerase that possess DNA polymerase and reverse transcriptase and RNaseH activities, and (4) the
X gene encoding for a transcriptional transactivator, hepatitis B virus X protein (HBx), which is essential for
virus replication [11,12] .

Among the four functional proteins encoded by HBV (X, surface, core, and polymerase), HBx and HBs
(mutant) proteins are designated “viral oncoproteins” . The pre-S/S mutants of HBV are considered
[13]
“precursor lesions” of hepatocellular carcinoma (HCC) and as risk factors for the post-operative recurrence
[14]
of HCC [15,16] . Various pre-S/S mutants contribute to HCC tumorigenesis via various mechanisms, including
transactivation of transcription factors, the endoplasmic reticulum (ER) stress-dependent pathway, the
ER stress-independent pathway, and others. Among these mutants, pre-S2 mutants showed significant
correlations with HCC and have been widely considered novel biomarkers of HBV-associated HCC [13,17] .
The malignant transformation potential of pre-S2 mutation has been confirmed in an immortalized
human hepatocyte line HH411 . In transgenic mice, pre-S2 mutants induced dysplasia of hepatocytes and
[18]
development of HCC , suggesting that pre-S2 plays a key role in HCC tumor progression.
[19]

In this mini-review, we discussed the relationship between pre-S2 mutations and HCC, as well as the
underlying molecular mechanisms and treatments based on HBV tumorigenesis induced by pre-S2.

STRUCTURE AND ROLE OF PRE-S IN HBV
HBV is a small, enveloped 3.2-kb DNA virus with four open reading frames. The HBV envelope is composed
of three forms of HBsAg, including the large (encoded by the pre-S1/S2/S gene), middle (pre-S2/S gene)
and small (S gene) envelope proteins [20,21] . In addition, truncated and mutated pre-S2/S [the large HBV
surface protein (LHBs) and truncated middle surface protein (MHBs)] or HBx proteins are produced by
integrated viral sequences [22-24] . The pre-S region has been reported to mediate hepatocyte attachment of
the virus, containing B cell and T cell epitopes [25,26] , a binding site for neutralizing anti-pre-S2 antibody [27,28] ,
and an S promoter for controlling the production of middle and small HBs proteins. Under endogenous
(host immunity) and/or exogenous (immunoprophylaxis and antiviral therapies) selection pressures, HBV
evolves by accumulating mutations in its genome, resulting in HBV variants with altered epitopes providing
higher pathogenicity [29-31] . In this context, a growing number of studies were performed to evaluate various HBV
genotypes; these pointed out the considerable importance of HBV envelope protein mutants (preS/S variants) [32,33] .
Naturally occurring pre-S mutations are frequently detected in serum obtained from patients with chronic
HBV infection . Furthermore, pre-S mutations were more common in chronic HBV infection and were
[34]
related to disease progression and HCC. Currently, the most frequently reported variations are the pre-S
deletion mutation and the pre-S2 start codon mutation [19,31,35-37] . In particular, the pre-S2 mutation often
coincides with changes in human immune cell epitopes and is more significantly correlated with HCC
[38]
than pre-S1 mutation .
[39]

THE ASSOCIATION BETWEEN PRE-S MUTATIONS AND HCC
The notion of pre-S/S mutations as causes of HBV immune escape was supported by the identification
of individuals who developed HBV infection in spite of having vaccine-induced circulating anti-HBs
antibodies [31,32,40] . Apart from the ability to avoid neutralization by vaccine-induced anti-HBs, these pre-S/S
mutations may also have accounted for cases of occult HBV infection [31,41] . Furthermore, pre-S/S mutations