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African Health Sciences
Makerere University Medical School
ISSN: 1680-6905 EISSN: 1729-0503
Vol. 10, Num. 1, 2010, pp. 93-98
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African Health Sciences, Vol. 10, No. 1, March, 2010, pp. 93-98
Hepatocellular carcinoma and the underlying mechanisms
*Oyagbemi AA, Azeez OI, Saba AB
Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University
of Ibadan, Oyo State, Nigeria.
*Corresponding author: Oyagbemi A.A, Department of Veterinary Physiology, Biochemistry
and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Oyo State, Nigeria. E-mail: ademolaoyagbemi@yahoo.com , aa.oyagbemi@mail.ui.edu.ng Phone: +2348033639776 Fax: 02-8103043
Code Number: hs10017
Abstract
The incidence of hepatocellular carcinoma is increasing worldwide as well as the associated risk factors, some of
which include exposure to aflatoxin B1, Hepatitis B (HBV) virus and hepatitis C (HCV) virus. Mutation of tumour
suppressor gene p53 at codon 249ser at exon 7 has been found to contribute significantly to replication of damaged DNA
and subsequent tumour progression. The x gene of HBV (HBx) is the most common open reading frame integrated into
the host genome in hepatocellular carcinoma and the integrated HBx is frequently mutated in hepatocellular carcinoma.
Mutant HBx proteins still retain their ability to bind to p53 thereby attenuating DNA repair and p53-mediated apoptosis.
Keywords: hepatocellular carcinoma, aflatoxin B1, HBV, HCV, p53
Introduction
Hepatocellular carcinoma (HCC) is one of the
most common malignancies worldwide. It is the
fourth leading cause of cancer-related death in the
world.1 The major risk factors include chronic infections
with the hepatitis B (HBV) or C (HCV) virus and
exposure to dietary AFB1 or alcohol consumption. A
link based on circumstantial evidence has been
divulged between high exposure to AFBI and mutation
at the 3rd nucleotide base of codon 249, which is
located on the 7th exon of p53 gene of cells of
primary liver cancer from patients in tropical countries
of the world and activation of the WNT signal transduction
pathway.2-6 AFB1 frequently induces G: C to T: A transversions at the third base in
codon 249. Interestingly, mutant DNA in plasma is
a biomarker of both AFBI exposure and potential risk factor for HCC with subsequent p53
mutation.7 The tumour suppressor gene p53 is the most commonly mutated gene in human
cancers. 8
Chronic infections with HBV and HCV viruses
and oxyradical disorders including hemochromatosis
also generate reactive oxygen/nitrogen species that
both damage DNA and mutate cancer - related
genes such as tumour suppressor gene
p53.9 The p53 biological network is a key responder to this
oxidative and nitrosative stress. Depending on the extent
of the DNA damage, p53 regulate transcription of protective antioxidant genes and the extent of
DNA damage that ultimately trans-activates
pro-oxidant genes which eventually contribute to apoptosis.
The x gene of HBV (HBx) is the most common open reading frame integrated into the host genome
in HCC and the integrated HBx is frequently
mutated. Mutant HBx proteins still retain their ability to
bind to p53 and attenuate DNA repair and
p53-mediated apoptosis. Hence, both viruses and
chemicals (especially vinyl chloride) are implicated in
the etiology of p53 mutation during the molecular pathogenesis of HCC.
HCC is a major cause of cancer
morbidity and mortality in many parts of the world,
including Asia and Sub Saharan Africa, where there
are >500,000 new cases each year and >200,000
deaths annually in the People's Republic of China
(P.R.C) alone.10 The major etiological factors associated
with development of HCC in these regions are
infection with HBV and or HCV and long time exposure
to high levels of AFBI in the
diet.11-12
Mechanisms underlying Hepatocarcinogenesis
The biology, mode of transmission,
and epidemiology of HBV continue to be actively investigated and have been recently
reviewed.13 A mutation in the HBV genome can alter the
expression of multiple proteins. In many cases of HCC in
China and Africa, a double mutation in the HBV
genome, an adenine-to-thymine transversion at
nucleotide 1762 and a guanine-to-adenine transition at
nucleotide 1764 (1762T/1764A) has been found in
tumours.14-15
This segment of the HBV genome contains an overlapping sequence for the base core
promoter region and the HBx gene; therefore, the
double mutation in codon 130 and 131 of the HBx
gene reported in human HCC is identical to the 1762
and 1764 nucleotide changes.16 The onset of
these mutations was shown to be associated with
the increasing severity of the HBV infection and
cirrhosis.14-15 HBx in transformed hepatocyte has
been demonstrated to inhibit the repair of damaged hepatocyte DNA. This effect may be mediated
by interaction with p53 or through binding to the damaged DNA binding protein (DDB), which
plays an accessory role in nucleotide excision
repair.13 In addition, HBx activates cell signalling
cascades involving mitogen-activated protein kinase
(MAPK) and Janus family tyrosine kinases
(JAK)/signal transducer and activators of transcription
(STAT) pathways.13 The process by which tumour DNA
is released into circulating blood is unclear but
may result from accelerated necrosis,apoptosis, or
other processes.17 A specific codon 249 p53
mutation detectable in plasma samples at the time of
HCC diagnosis, can be measured in some individual
at least 5 years before diagnosis.18
Heterogeneity in etiological factors of HCC
The frequency of HCC is particularly high in
Asia and Africa due to the high frequency of viral
hepatitis infections and to Aflatoxin B1 exposure
(AFB1). Over the last 10 years, the incidence of HCC
has noticeably increased in United Kingdom, France
and United States. This is probably linked to viral
hepatitis C infections. Etiological factors that are
associated with the development of hepatic tumours are
well known in these regions. They include infection
with the hepatitis B virus (HBV) or hepatitis C virus
(HCV), heavy alcohol intake, prolonged dietary exposure
to AFBl or vinyl chloride and primary hemochromatosis. In 90% of the HCC cases, at
least one of these risk factors can be identified either
alone or in combination with another factor. The
presence of each risk factor among patients varies
according to the geographical origin of the patients.
Globally, exposure to HCV, HBV and AFBI are
responsible for about 80% of all HCC in humans'
worldwide but the principal risk factor varies between
countries. In Japan almost all HCC are linked to HCV
infection, whereas in Africa HBV infections are
predominant.19 In France, HBV and HCV infections and
alcohol intake are identified with approximately
equal frequency. Exposure to AFBI is commonly found in sub-tropical countries where humid heat can
lead to the development" of Aspergillus
flavus in improperly stored foods such as cereals and
peanuts. This mycotoxin is strongly hepatocarcinogenic
in experimental animal models and acts
synergistically with HBV infection to increase the risk of
HCC.20 Tobacco exposure is the leading
carcinogen associated with multiple solid
tumours21. Several investigators have previously reported an
association between tobacco and HCC with odds ratios
ranging from 1.5 to 6.8.22-23 However, other studies
found no association between tobacco and
HCC.24
Hepatocarcinogenesis
The different risk factors of HCC include
chronic lesions in the liver with associated
inflammation, necrosis of hepatocytes and fibrosis. Overall,
HCC development is closely associated with cirrhosis
and more than 80% of the tumours are found in a
chronic hepatitis or a cirrhotic
background.25 Dysplastic nodules and macroregenerative nodules have
long been considered to be the likely precursors of
HCC because of their frequent association with the
HCC occurrence.26 Chromosome aberrations occur
in HCC and these may already contain genetic aberrations. However, in rare cases (less than
10% of the cases), HCC are observed in
non-cirrhotic liver and even without inflammatory lesions.
The HCC which develop in an otherwise normal liver are usually found in patients without
well-established risk factors. Some of these cases may
correspond to the malignant transformation of liver
adenoma that are rare benign hepatocellulartumours
sometimes found in young women taking oral
contraceptives.27
HBV infection
The incidence of HCC has been shown to vary
widely worldwide. 28 Among males, the highest
incidence rates are found in eastern Asia, particularly in
China where HCC was reported to be the third most common cause of cancer
death29. Chronic infection with the HBV has been reported by various
authors as the strongest risk factor for HCC
worldwide. 28, 30-32 However, populations with similar
prevalence of HBV infection have different incidence of
HCC, suggesting the presence of other important
risk factors. Aflatoxins, a group of mycotoxins
produced by the common fungi Aspergillus flavus and Aspergillus parasiticus, are established human
hepatocarcinogens and are well-known HCC risk factors when
present in foodstuffs.32-35 Some epidemiological and animal studies have found evidence for an HBV-aflatoxin interaction in
hepatocarcinogenesis. 35-41
Several mechanisms underlying this principle
have been proposed to explain the interaction
between HBV and aflatoxin. The increase in
cellular proliferation induced by HBV could increase
the probability for clonal expansion of an
existing aflatoxin induced-p53 249ser mutation42. An
increase in levels of aflatoxin metabolism enzymes
(e.g., P450 enzymes in which its activity is associated
with increased hepatotoxicity of aflatoxin) has
been described for HBV transgenic mice and has
been postulated as a mechanism for
interaction.43 The HBx protein, which is encoded by HBV interferes
with the nucleotide excision repair pathway, a major
repair pathway which cells use to repair damaged
DNA.44 However, the presence of mutant HBx protein
could increase the frequency of aflatoxin-induced
mutations.44 Also, HBV infection was reported
to increase oxidative stress, which could lead to
an increase in p53 mutations.45
Mechanisms of HBV-mediated hepatocarcinogenesis
HBV infection can promote carcinogenesis by at
least 3 different mechanisms. First, integration of the
viral DNA in the host genome can induce chromosome instability. Second, insertional mutations of HBV
are known to activate endogenous genes of retinoic
acid α-receptor, cyclin A and mevalonate kinase
which are involved in cell cycle control, cellular
proliferation and differentiation. The second mechanism
is associated with specific intracellular
receptors. Recently, 15 new genes were found to be altered
by HBV integration in tumors suggesting that viral integration in the vicinity of genes controlling
cell proliferation, viability and differentiation is
a mechanism frequently involvedin HBV hepatocarcinogenesis. The third mechanism
of carcinogenesis linked to HBV infection is based
on the expression of viral protein, in particular HBx,
to modulate cell proliferation and viability.
Moreover, HBx binds to p53 and inactivates
p53-dependent activities, including p53-mediated apoptosis.
Recently, the association between hepatitis B virus
and Hepatocellular carcinoma and the molecular mechanism of action that is involved in
the hepatocarcinogenesis has been extensively
described.46,47
Interaction of AFB1 with DNA and
chromatin proteins (histone)
After an exposure to AFB1, accumulations
of damaged DNA are found in the liver, as a result
of conversion of the AFBI to its active
metabolites. AFBI is a very potent mutagen and the
AFBI epoxides (active metabolites of aflatoxin) react
with guanine in DNA, leading to genetic changes.
The most frequent mutation induced is the (guanine-cytosine to thymine-adenine) GC to TA
transversion. However, quantitative determination of AFB1
in human aflatoxin albumin adducts has been
ellucidated.48 The mutational pattern of p53 gene
in HCC from regions where AFBI exposure level is high, revealed (guanine to thymine) G to
T transversion at codon 249 in more than 50% of
the cases. A more detail study revealed that AFB1
binds preferentially to lysyl amino acid residues in
histone proteins.10 The binding of AFB1 to histone
proteins has significant functional implications because
histone has been reported to be the packaging material
for DNA and histone H1 is the most external of the histone proteins wrapped around
DNA.10,49 Because of the high content of basic amino acids in
histones, it is conjectured that there is a strong
electrostatic interaction between them and DNA and
that (addition of acetyl group) acetylation of the
lysyl sites which is involved in this type of
interaction, reduces the net positive charge of the histone
and loosens the bonds between histone and DNA. Acetylation is reported to occur at the amino
group of lysly amino acid residues which is the same
binding site of AFBl.50, 10
The effect of AFBl binding to histone
is therefore likely to be similar to reaction elicited
by Acetylation (a post transcriptional
modification), which is the partial loosening of the
histone-DNA bond and the consequent degradation of the
histone by specific proteases.51It is generally accepted
that such a partial loosening of the histone DNA
bonds always precedes gene expression. This means that
it is most likely that it is the binding of AFBl to
lysly amino acid residues in histone with the
consequent loosening of the histone-DNA bond that makes
p53 accessible for damage. It is also likely that the
binding of AFB1 to histones with the consequent
loosening of histone is primary to its binding to the DNA
of p53 genes even though the binding to DNA subsequently exceeds its binding to histone.
Taken together, the binding of AFBI to DNA is
responsible for the inhibition of RNA Synthesis, which
is involved in gene expression.
The implication of the above is that it is the
binding to chromatin proteins (histone) may be involved
in the expression of the mutated p53 gene
resulting from the interaction of AFBI with DNA
and chromatin proteins. The p53 gene is reported to
be mutated in HCC after exposure to
aflatoxin.52 Recently, some authors have extensively
discussed the association between AFB1 and the
associated risk factors involved in
HCC.53-55
Conclusion
The nexus between hepatocellular carcinoma and
the associated risk factors cannot be
overemphasized. The interaction between aflatoxin and HBV or
HCV in hepatocarcinogenesis and multi-stage carcinogenesis is grossly elucidated.
Characterization of the genetic alterations associated with
HCC tumors is an essential step to increase our
knowledge of hepatocarcinogenesis. Systematic search for
these alterations in series of tumors including
tumour grades, stages, etiologies and the associated
pre-neoplastic lesions is therefore necessary to find
and identify the pattern of accumulation of the
genetic alterations during tumour progression.
Microarray analysis and metagenomics may also
contribute significantly to identifying new
carcinogenetic pathways altered in these tumors. New insight
should therefore be geared towards getting a better
clinical application, to identity tumour markers that are
useful for early detection of tumors, to predict
prognosis, or to find new therapeutic targets with
their underlying molecular mechanism of action.
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