18 research outputs found
The hamster model of sequential oral oncogenesis
Oral squamous cell carcinoma (OSCC) is a common cancer characterised by
low survival rate and poor prognosis. The multistep process of oral
carcinogenesis is affected by multiple genetic events such as
alterations of oncogenes and tumour suppressor genes. The use of
appropriate experimental animal models that accurately represent the
cellular and molecular changes which are associated with the initiation
and progression of human oral cancer is of crucial importance. The
Syrian golden hamster cheek pouch oral carcinogenesis model is the best
known animal system that closely correlates events involved in the
development of premalignant and malignant human oral cancers. Therefore,
we established an experimental system of chemicatly induced oral
carcinogenesis in hamsters, in order to study different stages of tumour
formation: normal. mucosa, hyperkeratosis, hyperplasia, dysplasia, early
invasion, well. differentiated OSCC and moderately differentiated OSCC.
We investigated the expression of oncogenes EGFR, erbB2, erbB3, FGFR-2,
FGFR-3, c-myc, N-ras, ets-1, H-ras, c-fos and c-jun, apoptosis markers
Bax and Bcl-2, tumour suppressor genes p53 and p16, and cell
proliferation marker Ki-67 in the sequential stages of hamster oral
oncogenesis. Here, we describe the findings of the experimental model in
regard to the involvement of signal transduction pathways in every stage
of cancer development. Increased apoptosis and cell proliferation were
observed in early stages of oral oncogenesis. Furthermore, the increased
expression of transmembrane receptors (EGFR, erbB2, FGFR-2 and FGFR-3)
as well as the increased expression of nuclear transcriptional factors
in early stages of oral cancer indicates that these molecules may be
used as early prognostic factors for the progression of OSCC. Since the
expression of both H-ras and N-ras do not seem to affect signal
transduction during oral oncogenesis, it can be assumed that a different
signalling pathway, such as the PI3K and/or PLC gamma pathway, may be
implicated in the pathogenesis of OSCC. (C) 2007 Elsevier Ltd. All
rights reserved
Methylenetetrahydrofolate reductase polymorphism and minor increase of risk for oral cancer
Purpose: We investigated whether the mutant methylenetetrahydrofolate
reductase (MTHFR) increases risk for oral cancer. The common germ-line
mutation C677T in the MTHFR gene significantly diminishes specific
activity of the enzyme, which is responsible for the circulating form of
folate. Folate deficiency is associated with increased risk for
thrombosis, as well as for several types of cancer, through disruption
of DNA methylation, DNA synthesis and deficient DNA repair. Methods: We
searched for the C677T mutation by restriction fragment analysis of PCR
products in DNA samples of 110 patients with oral squamous cell
carcinoma and 120 healthy controls of comparable ethnicity, age and sex.
Results: The number of heterozygotes was significantly different in the
two groups (P < 0.005), as well as in subgroups of patients with or
without a positive family history for cancer, compared to normal
controls (P < 0.01 and P < 0.005, respectively). Furthermore, the
subgroup of patients with a positive family history for thrombophilia
had a significant increase both in the frequencies of mutant alleles (P
< 0.01) and heterozygotes (P < 0.001) in comparison to normal controls.
Conclusions: The obtained results suggest that the MTHFR mutation is a
minor contributing factor in oncogenesis in the oral region, in
conjunction with low dietary uptake of folate
Diabetes enhances the expression of H-ras and suppresses the expression of EGFR leading to increased cell proliferation
EGFR kinase activity triggers numerous
signaling pathways, such as the Ras/Raf/MAPK cascade,
leading to the activation of various mitogen activated
protein kinases, which are implicated in cell proliferation
through induction of several genes, including c-fos. The
possible effect of diabetes on the expression of the
oncogenes EGFR, H-ras and c-fos was investigated in an
experimental model of chemically induced oral
oncogenesis in normal and diabetic (type I) Sprague-
Dawley rats. Thirteen diabetic and twelve normal rats
developed cancer after 4NQO treatment, while six
diabetic and six normal animals were used as controls.
The biopsies were classified pathologically (ranging
from dysplasia to moderately differentiated oral
squamous cell carcinoma) and were studied
immunohistochemically. Several representative
histological regions from each biopsy were analysed in
regard to EGFR, H-ras and c-fos expression, and a
comparison between normal and diabetic rats was
effected. A trend of decreased EGFR expression in
diabetic compared to normal rats was revealed
throughout oncogenesis, which was significant in the
stage of dysplasia (P<0.05). On the contrary, a trend of
increased H-ras expression was observed in diabetic compared to normal rats during oncogenesis, which rose
significantly in early invasion and well differentiated
OSCC (P<0.001 and P<0.01 respectively). Finally, no
statistical differences concerning c-fos expression were
detected between diabetic and normal animals. In
conclusion, it seems that diabetes reduces the expression of EGFR and initiates the Ras/Raf/MAPK signal
transduction pathway by enhancing activation of other
signalling molecules, such as the diabetes-associated
Insulin Receptor Substrate-1, leading to increased cell
proliferation without c-fos involvement
Association study indicates combined effect of interleukin-10 and angiotensin-converting enzyme in basal cell carcinoma development
Cytokines involved in inflammatory and immune response have been associated with risk for development of basal cell carcinoma (BCC). In this study, three functional DNA polymorphisms affecting gene expression were investigated in 54 BCC patients and 111 healthy controls: interleukin-1b (IL-1b) +3953C/T, interleukin-10 (IL-10) − 1082G/A and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms. Significant increase of the variant alleles was observed in IL-10 − 1082G (P = 0.019) and in ACE D (P = 0.003) in BCC patients in comparison to controls. Multivariate logistic regression models evaluated the contribution of homozygous and heterozygous variant polymorphisms to the risk for BCC development. The studied polymorphisms influencing the expression of IL-10 and ACE genes were recognized as potential predictive factors for BCC. These findings suggest a possible molecular mechanism leading to BCC development that is likely to involve the activation of angiotensin receptors in combination with increased plasma levels of IL-10 in patients. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature
Association of leptin -2548G/A and leptin receptor Q223R polymorphisms with increased risk for oral cancer
Purpose: We investigated the possible association of DNA polymorphisms -2548G/A and Q223R in the leptin (LEP) and leptin receptor (LEPR) genes, respectively, which both affect the amount of circulating cytokine-type hormone leptin, with risk for development of oral cancer. Methods: Polymerase chain reaction-based restriction analysis was performed in DNA samples of 150 patients with oral squamous cell carcinoma (OSCC) and 152 healthy control subjects of equivalent gender, age, and ethnicity (Greeks and Germans). Results: Compared to controls, the homozygous high gene expression genotype A/A of the LEP -2548G/A polymorphism was significantly increased in the subgroups of patients with advanced cancer stages (P = 0.0001; OR 9.0, 95% CI 2.62-30.89), with a positive family history of cancer (P = 0.0346; OR 3.55, 95% CI 1.15-11.01), without tobacco abuse (P = 0.0051; OR 9.69, 95% CI 1.03-91.24), and without alcohol abuse (P = 0.0472; OR 2.16, 95% CI 0.87-5.37). The homozygous low-leptin-binding genotype G/G of the LEPR Q223R polymorphism was strongly associated with an increased risk for OSCC for all patients (P = 0.0028; OR 4.11, 95% CI 1.30-12.97) as well for most of the patient subgroups. Conclusions: The above findings are consistent with the growth-promoting role of leptin in cancer and its induction effect on angiogenesis and metastasis. This is the first study indicating the association of these LEP and LEPR gene polymorphisms with increased risk for OSCC. © 2008 Springer-Verlag
The low VEGF production allele of the+936C/T polymorphism is strongly associated with increased risk for oral cancer
Purpose Based on the well-established role of vascular endothelial
growth factor (VEGF) in tumor-associated angiogenesis in several cancer
types and its undefined role in oral oncogenesis, we investigated the
possible association of an expression-regulating polymorphism (+936C/T)
with risk for oral squamous cell carcinoma (OSCC).
Methods We studied the allele frequencies of the +936C/T polymorphism in
DNA samples of 144 patients with OSCC and 153 healthy controls matched
by age, gender and ethnicity, using restriction fragment length
polymorphism typing analysis.
Results The low-expression T allele was significantly increased in the
total patient group compared to controls (P = 0.008), due to a
significant over-representation of C/T heterozygotes compared to C/C
homozygotes (P = 0.007). The same pattern was observed in most patient
subgroups and more noticeably in patients with a positive family history
of cancer (P = 0.001). Interestingly, the increase in T allele frequency
was only significant in patients at cancer stages I and II (P = 0.006).
Conclusions This study clearly indicates that the low-VEGF-production T
allele is strongly associated with increased risk for OSCC. In addition,
the impressive T allele frequency increment in patients with a positive
family cancer history suggests that this allele may also be involved in
other malignancies. The fact that this significant increase was observed
only in patients with early cancer stages may imply that low VEGF levels
might hinder subsequent tumorigenesis. Our findings might be the result
of either unidentified properties of the +936 C/T polymorphism or of a
strong linkage disequilibrium between this polymorphism and another
genetic locus
A metalloproteinase-9 polymorphism which affects its expression is associated with increased risk for oral squamous cell carcinoma
Aim: In light to recently found contribution of factors associated with
angiogenesis, thrombosis and inflammation to carcinogenesis, we
investigated the possible association of metalloproteinase-9 (MMP-9)
with increased risk of oral cancer.
Methods: In DNA samples of 152 patients with oral squamous cell
carcinoma and 162 healthy controls of comparable ethnicity, age and sex,
we studied the -1562 C/T polymorphism in the MMP-9 gene promoter, which
affects its transcription.
Results: The detected frequency for the high expression T allele in the
patients’ group was significantly increased in comparison to that of the
control group (22% versus 15%, respectively; P < 0.05). This
difference was due to the relative increase of C/T heterozygotes in the
group of patients, in comparison to controls (P < 0.05, 95% OR 1.92, CI
1.21-3.06). The same pattern of significance was observed between
controls and the subgroups of patients with initial (I & II) stages of
cancer, without positive family history of cancer or thrombophilia, with
smoking and alcohol abuse habits.
Conclusions: The investigated MMP-9 polymorphism has a strong
association with increased risk for developing oral cancer in a subset
of the general population. These results are in accordance to previous
studies of constitutive expression and secretion of MMP-9 in invasive
oral carcinoma cell lines. The observation that T allele carriers have
an increased risk for developing oral cancer only in initial stages, but
not in advanced ones, may be due to the role of MMP-9 in the inhibition
of angiogenesis by generating angiostatin from plasminogen. (C) 2007
Elsevier Ltd. All rights reserved
Gene polymorphisms related to angiogenesis, inflammation and thrombosis that influence risk for oral cancer
Genetic association studies have implicated functional DNA polymorphisms
in genes encoding factors related to angiogenesis, inflammation and
thrombosis with increased risk for oral squamous cell carcinoma (OSCC).
This study examines possible interactions between nine such genotype
polymorphisms and their combinatory effect in assessing the OSCC risk in
a European population.
OSCC cases (N = 162) and healthy controls (N = 168) of comparable age,
gender, and ethnicity (Greeks and Germans) were studied. Multivariate
logistic regression models were constructed in order to assess the
contribution of homozygous or heterozygous variant genotypes of
polymorphisms MMP-1 (-1607 1G/2G), MMP-3 (-1171 5A/6A), MMP-9
(-1562C/T), TIMP-2 (-418C/G), VEGF (+936C/T), GPI-alpha (+807C/T), PAI-1
(4G/5G), ACE (intron 16D/I) and TAFI (+325C/T) upon overall, early and
advanced stages of OSCC.
Four out of nine polymorphisms affecting PAI-1, MMP-9, TIMP-2 and ACE
expression contributed significantly in OSCC prediction in the various
logistic regression models. Based on these findings and previous
reports, possible interactions of the implicated factors leading to OSCC
development, as well as an algorithm of risk estimation are discussed.
(C) 2008 Published by Elsevier Ltd
Plasminogen activator inhibitor-1 polymorphism is associated with increased risk for oral cancer
In light of the recently observed contribution of thrombosis-related
factors to carcinogenesis, we investigated the possible association of
plasminogen activator inhibitor-1 (PAI-1) with increased risk for oral
cancer. In DNA samples of 104 patients with oral squamous cell carcinoma
and 106 healthy controls of comparable ethnicity, age and sex, we
studied the 4G/5G polymorphism in the PAI-1 gene, which affects its
expression. The mutant 4G allele and carrier frequencies were
significantly increased in patients compared to controls (65.9% versus
49.5%; 88.5% versus 69.8% respectively, P < 0.01). That increase was
even higher in patients with a positive family history for thrombophilia
or without one for cancer (P < 0.001). Interestingly, significant
difference from controls was observed only in patients with cancer
stages I and II. These findings suggest that the 4G allele, by resulting
in higher PAI-1 expression, is a major contributing factor in early
stages of oral oncogenesis. Possibly, increased PAI-1 promotes initial
development of oral cancer through regulation of cell detachment and
delays further tumor progression by inhibiting vascularization. (c) 2006
Elsevier Ltd. All rights reserved
Cell proliferation and apoptosis culminate in early stages of oral oncogenesis
Markers of cell proliferation (Ki-67 antigen) and apoptosis (Bax, Bcl-2)
were studied in an experimental system of induced oral carcinogenesis in
Syrian golden hamsters. Thirty-seven animals were divided into one
control group and three experimental groups, which were treated with a
carcinogen and sacrificed at 10, 14 and 19 weeks after treatment. The
histological status of the lesions in the three experimental groups
corresponded well with tumour advancement (from oral mucosal dysplasia
to moderately differentiated squamous cell carcinoma). Tumour sections
were studied using monoclonal antibodies against Bax, Bcl-2 and Ki-67
proteins. Pro-apoptotic Bax expression maintained high levels during all
stages of oral carcinogenesis. Anti-apoptotic Bcl-2 expression decreased
significantly in dysptastic and early invasion lesions and consequently
increased almost to normal tissue level in consequent stages. Finally,
Ki-67 expression increased sharply in initial stages of oral
carcinogenesis, but significantly decreased in later stages. (c) 2005
Elsevier Ltd. All rights reserved