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

PDZ-binding motifs (TAZ), thereby playing oncogenic roles in HCC cells by repressing miRNA-338-3p
expression, implicating hepatocarcinogenesis [64-66] .

Pre-S2 mutants
Both pre-S1 and pre-S2 mutants led to defective secretion of mutant large surface antigens that then
accumulated in the ER, leading to GGH formation in chronic HBV infections. As mentioned above, type II
GGHs that harbored pre-S2 mutations accumulating on the ER of hepatocytes were considered biomarkers
of HCC . HBV proteins utilize the ER protein folding machinery and cellular secretory pathway .
[47]
[67]
Therefore, the underlying mechanisms of pre-S mutations contributing to HCC may be involved in ER
stress . ER stress, also called the UPR in mammalian cells, is a cellular defense mechanism that responds to
[7]
unfolded viral proteins or perturbed ER functions . Expression of viral gene products is detected by three
[19]
UPR sensors, including two ER transmembrane kinases (IRE1 and PERK), and one ER transmembrane
transcription factor (ATF‐6). The three UPR sensors are associated with ER chaperone GRP78/BiP at rest,
and are dissociated from GRP78 upon ER stress . Induction of GRP78 prevented cells from apoptosis,
[68]
and ER stress‐regulated translation increased tolerance to extreme hypoxia and then promoted tumor
growth [69,70] . The activation of ER‐stress downstream molecules such as ATF‐6, GRP78 and XBP‐1 is believed
to be involved in hepatocarcinogenesis .
[71]
Both types of pre-S mutants cause overproduction and accumulation of mutated envelope proteins in
the ER, and the accumulation of mutant or unfolded proteins cause stress in the ER that is sensed by the
glucose-regulated protein 78 (GRP78). Unfolded proteins sequester GRP78 and dissociate from three ER
transmembrane transducers leading to their activation; this leads to significant ER stress that may lead
to oxidative stress and DNA damage , resulting in genomic instability and ultimately development
[72]
[73]
of HCC [74,75] . A detailed study aimed at delineating the molecular mechanisms of pre-S mutant-induced
genomic instability suggested that pre-S2 mutant large surface protein inhibited DNA double-strand break
repair and led to genome instability in hepatocarcinogenesis; this represented a promising high-risk HCC
biomarker in chronic HBV carriers . The ER stress initiated by the pre-S mutants activated two pathways
[76]
that protect hepatocytes from apoptosis, one involving nuclear factor (NF)-κB to upregulate cyclooxygenase-2
(COX-2) [45,77] and the other involving vascular endothelial growth factor to activate AKT/mammalian
target of rapamycin (mTOR) signaling . The mammalian target of mTOR is a highly conserved serine/
[74]
threonine kinase that controls cell growth and proliferation . Pre-S2 mutations promoted tumorigenesis
[78]
by sustaining high activation rates of aerobic glycolysis through the mTOR signal cascade . In addition,
[79]
the pre-S2 mutation LHBs induced an ER stress-independent c-Jun activation domain binding protein 1
(JAB1)/p27/retinoblastoma (Rb)/adenovirus E2 promoter binding factor/cyclin A signal to initiate cell cycle
progression . These studies suggested that the combined effects of genomic instability and cell proliferation
[75]
potentially resulted in carcinogenesis .
[7]

TREATMENT STRATEGIES BASED ON ER STRESS
One of the strategies used to prevent HBV-associated liver diseases and HCC is vaccination . The
[80]
effectiveness in preventing blood-borne transmission from an infected mother to her newborn was about
90% , however therapeutic vaccines for the treatment of established HBV infection are not available [82,83] .
[81]
Two antiviral therapies have been approved: pegylated alpha interferon and nucleoside/nucleotide analogues
(NA) . NA therapy has antiviral effects that reduce HCC development and post-operative recurrence of
[84]
HCC . NA treatment affects the reverse transcription of pregenomic RNA but does not affect cDNA and
[85]
subgenomic RNA that have translational activity associated with HBsAg levels. Thus, current NA therapy
can hardly clear HBsAg . Subsequent studies also showed that pre-S2 mutations induced resistance to
[13]
NAs and predicted HCC development . Related studies showed that interferon treatment, more than NA
[86]
treatment, inhibited HBsAg and pre-S mutant protein [53,87,88] . However, these antivirals therapy often failed
to eradicate the virus completely, and their efficacy in preventing liver cirrhosis and HCC was limited [89,90] .