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Link et al. Roles of p53 in extrinsic factor-induced liver carcinogenesis

direct effect on p53 activity. C57BL/6 mice fed a high- sequestering p53 to the cytoplasm in transgenic
iron diet show a decrease in p53 protein levels in the mouse models [Figure 1B]. [81,82]
liver. [68] Also, male Sprague-Dawley rats fed a high-
iron diet for prolonged periods of time present with HBx is also implicated in hepatocyte apoptosis. [78]
an increase of MDM2, and a subsequent decrease In many contexts, HBx inhibits apoptosis not only by
of p53 in the liver. [69] Another molecular mechanism increasing levels of anti-apoptotic protein, survivin,
behind decreased levels of p53 due to iron excess but also by binding to and sequestering p53 to the
includes that p53 is bound by heme, exported to cytoplasm. [83-86] HBx is also reported to inhibit TGF-
the cytoplasm, and degraded in HepG2 cells via the β-mediated apoptosis. [87] Conversely, in some
proteasomal pathway. [68] Thus, both iron excess and contexts, HBx is shown to induce apoptosis in a p53-
dysregulated heme decrease p53 levels, contributing independent manner. [88-90] Hence, the dual roles of
to HCC development [Figure 1B]. Intriguingly, p53 HBx in hepatocyte apoptosis and its association with
is also involved in reducing intracellular iron levels HCC genesis warrant further investigation.
by transactivating iron-sulfur cluster enzyme 2
which contributes to reduced iron uptake. [70,71] Thus, HBx variants with C-terminal truncations (Ct-HBx) are
following chronic iron overload, reduced p53 activity frequently detected in HCC and might also contribute
leads to increased intracellular iron levels, further to HCC development, though there is no direct
promoting HCC genesis. It should be noted that evidence for it. [91-93] Ct-HBx promotes hepatocyte
patients with hereditary hemochromatosis show proliferation and inhibits apoptosis in multiple cell
higher rates of p53 mutations (64-71%), as compared lines. [94-96] Transcriptional downregulation of ubiquitin
with those in sporadic HCC, supporting a role of p53 specific peptidase 16 (USP16) by Ct-HBx is also
in iron overload-induced HCC genesis. [72,73] In HCC shown to enhance tumorigenicity and stem-like
tissues from hereditary hemochromatosis, 45% A>C properties of HCC cells. [97] Moreover, Ct-HBx binds
transitions and 33% G>C transversions, including two to p53 and inhibits p53-mediated apoptosis similar
hotspots at codon 275 and 298, are identified in the to HBx [Figure 1B]. [85,98,99] Additionally, some Ct-HBx
p53 gene [Figure 1A]. [73] However, in the study using variants have the ability to silence mRNA expression
British families with hereditary hemochromatosis, of GAS2, a modulator of p53-mediated apoptosis. [100]
the p53 mutation spectrum consists of 60% Thus, Ct-HBx may contribute to the pathogenesis
A>G transitions and 40% A>T transversions. [72] of HBV-related HCC by downregulating USP16 and
Nonetheless, it remains to be elucidated whether iron inhibiting p53-mediated apoptosis.
overload indeed induces HCC in a p53-dependent
manner in animal models. Given that p53 is infrequently mutated in HBV-related
HCC, p53 mutations are associated with late stage
HBV disease, and both HBx and Ct-HBx bind to and inhibit
p53 function [Figure 1B], [101-103] inactivation of p53
Globally, it is estimated that 248 million individuals activity may be favorable for HBV-mediated HCC
have chronic HBV infection and are positive for the tumorigenesis, rather than p53 mutation. Importantly,
hepatitis surface antigen. [74] HBV is the leading cause HCC patients with wild-type p53 have better overall
of HCC, with the majority being attributed to chronic survival and an increase in recurrence free survival
HBV infection. [75] HBV-mediated HCC tumorigenesis as compared with those having p53 mutations. [104]
can be caused by repeated bouts of immune-mediated
hepatocyte death and subsequent tissue repair, with HCV
eventual cirrhosis of the liver. [76] Importantly, 10-30%
of HBV-related HCCs do not occur in the background Hepatitis C is estimated to have a global prevalence
of cirrhosis, indicating additional oncogenic of 184 million individuals positive for anti-HCV, and
mechanisms behind HBV-induced HCC genesis. [77] individuals with HCV have a 15 to 20 fold increased
risk for HCC. [105,106] HCV is a 9,600 nucleotide positive
HBV, a circular, partially double-stranded DNA virus, sense single-stranded RNA virus with a single open
consists of four overlapping open reading frames in its reading. [107,108] The HCV genome encodes for a
genome: a core region, surface region, polymerase polyprotein that is subsequently cleaved into nine
region, and X region which produce seven viral viral proteins, including structural proteins (C, E1, E2),
proteins named precore, core, polymerase, L, M, HBx, and non-structural proteins (p7, NS2, NS3, NS4A,
and S. [78-80] Of these, the HBx protein, which plays NS5A, NS5B). [109] Although the vast majority of HCV-
a pivotal role in viral replication, is most implicated related HCCs occur within the context of cirrhosis,
in HCC genesis. [80] Indeed, HBx induces HCC by there is some evidence showing oncogenic potential
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