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

+/+
-/-
VINYL CHLORIDE model for NAFLD where p53 and p53 mice are
fed a methionine- and choline-deficient diet, p53 +/+
Vinyl chloride (VC) is a carcinogenic gas used in mice show increases in histologically observable
the manufacture of PVC which induces mainly steatohepatitis, reactive oxygen species (ROS)
angiosarcomas of the liver (ASL) and rarely HCC, formation, and fibrosis with increased protein levels
although it remains controversial whether VC can of p66Shc, a protein associated with oxidative
induce HCC in humans. [38-40] VC is absorbed in stress, as compared to p53 mice. [53] Human NASH
-/-
the lungs and then metabolized to chloroethylene hepatocytes display upregulated p53 activity with
oxide by CYP2E1 in the liver, which forms bulky increased mRNA levels of p21 and p66Shc, which is
DNA adducts, leading to liver cancer. [41,42] There positively correlated with fibrosis severity. [53] The miR-
are four VC-associated DNA adducts detected in 34-Sirtuin 1 (SIRT1)-p53 pathway is also implicated in
4
vivo, including 7-(2-oxoethyl)-deoxyguanosine, 3,N - NAFLD pathogenesis; increased miR-34 expression
6
etheno-deoxycytidine, 1,N -etheno-deoxyadenosine, and subsequent decrease in SIRT1 protein levels are
2
and N ,3-etheno-deoxyguanosine. [41]
detected in human NAFLD liver tissues with increased
acetylation of p53, which is correlated with disease
VC-induced human ASLs are reported to have severity. [54] Activation of the miR-34a-SIRT1-p53 axis
an increase in A>T transversions at codons 179,
249, and 255 of the p53 gene [Figure 1A]. [43,44] is also shown to contribute to liver fibrosis or NASH
[55,56]
A study using Sprague Dawley rats also indicates by inducing hepatocyte apoptosis. Moreover, p53
that the majority of p53 mutations in ASL and HCC can upregulate miR-34, which inhibits SIRT1 mRNA
following VC exposure are A>T transversions; the expression, leading to increased acetylation of p53,
[57]
A>T transversions in ASLs are detected at codon thus forming a positive feedback loop [Figure 1B].
253 of rat p53, which is equivalent with codon 255 in These observations indicate that high expression of
humans. [45] Moreover, serum samples from workers miR-34 and p53 is associated with NAFLD. However,
exposed to VC have an increase in the levels of p53 it should be noted that miR-34a-mediated apoptosis
protein with mutant conformation, detected by a can occur in p53-dependent and p53-independent
conformation-specific p53 antibody PAb240, as well manners. [58] Nonetheless, surrounding evidence
as other antibodies for p53. [44,46] However, it is still suggests involvement of p53 in the progression of
unclear whether p53 plays protective roles in VC- NAFLD and NASH; however, further studies are
induced DNA damages and liver cancer development, required to demonstrate whether p53 directly plays a
and how mutations in p53 contribute to the VC- crucial role in the NAFLD-mediated HCC.
induced liver cancer [Figure 1B].
IRON OVERLOAD
NAFLD
Iron is an essential mineral that takes part in numerous
NAFLD represents a range of disorders including metabolic processes, such as heme synthesis,
non-alcoholic fatty liver (NAFL), non-alcoholic Fe-S cluster biogenesis, and oxygen transport via
steatohepatitis (NASH), fibrosis, cirrhosis, and HCC. hemoglobin. [59] However, when iron homeostasis is
NAFLD is associated with metabolic syndrome, type perturbed, whether due to genetic or environmental
2 diabetes mellitus, and obesity. [47] It is estimated that causes, there can be severe consequences including
20-30% of individuals in the Western world suffer cardiomyopathy, hepatic fibrosis, endocrine disorders,
from NAFLD. [48] However, only 11.5% of patients and arthropathy. [60,61] Importantly, excess iron is a risk
with NAFLD-induced cirrhosis eventually develop factor for many types of neoplasia, including breast
HCC, and about 50% of NASH-induced HCCs occur cancer, colorectal cancer, and HCC. [62] In parts of sub-
without cirrhosis. [49,50] These observations indicate the Saharan Africa, dietary iron overload, mainly from beer
requirement of additional oncogenic events toward prepared in iron pots, is strongly associated with an
NAFLD-associated HCC. However, the molecular increased risk of HCC. [63] Experimentally, Wistar rats
mechanisms behind NAFLD-mediated HCC are fed a high-iron diet are shown to develop HCC. [64] One
not fully understood. Several mediators have been mechanism implicated in iron overload-mediated HCC
implicated in its genesis, including dysregulation of genesis is due to ROS-inducing DNA mutations, as
NF-κB signaling, the Pl3K-ATK-PTEN pathway, insulin multiple rat models and surveys of human HCCs have
resistance, and expression of certain miRNAs (e.g. linked increased iron levels with increases in 8-oxo-2-
miR-34). [51,52] deoxyguanosine adducts and oxidizing products such
as malondialdehyde. [65-67]
p53 has also been implicated in the progression of
NAFLD due to multiple mechanisms. In a mouse However, there is evidence that iron overload has a

98 Hepatoma Research ¦ Volume 3 ¦ June 6, 2017