Bladder Cancer and Nos-no
Gene Polymorphısms
Akın
Soner Amasyalı, Ercan Kazan, B¨¹lent Erol
Akın Soner Amasyalı,
Ercan Kazan, Department
of Urology, Adnan Menderes University School of Medicine, Turkey
B¨¹lent Erol, Bulent Erol, Associate Professor of Urology, Department of Urology, Istanbul
Medeniyet University Faculty of Medicine, Istanbul, Turkey
Correspondence to: Bulent Erol MD, Associate
Professor of Urology, Department
of Urology, Istanbul Medeniyet University Faculty of Medicine, Istanbul, Turkey
Email: erolbulent@yahoo.com
Telephone: +905323526564
Received: March 26,
2015
Revised: May 12, 2015
Accepted: May 16, 2015
Published online: June 26, 2015
ABSTRACT
Nitric oxide (NO)
is a pleiotropic molecule with a variety of functions. NO may have both pro-
and antitumor functions. NO could take part in tumour development and
progression. Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene
may infuence the risk of cancer, but the results are still conflicting. Most
studied eNOS gene mutations are T-786C, G894T and intron 4a/b polymorphisms in
the literature. Environmental factors and genetic susceptibility may contribute
to cancer development. Numerous clinical and molecular studies have shown that
bladder cancer is a heterogeneous disease. Different chemical carcinogens are
associated with similar levels of risk for developing varying grades and stages
of bladder cancer, and therefore, carcinogen exposure alone cannot explain the heterogeneity of the disease.
Molecular alterations may lead to heterogeneity and are influenced by
environmental exposure. There are many genetic polymorphisms in metabolic
enzymes, and other genes have been found to be bladder cancer risk factors. But
a few studies have evaluated the role of eNOS polymorphisms in a this cancer.
The objective of this review is to evaluate the role of the eNOS polymorphisms
in cancer susceptibility, especially in bladder cancer which is the second most
common malignancy of urinary tract.
© 2015 ACT. All
rights reserved.
Key words: Nitric oxide; Nitric oxide syntase polymorphism; Bladder
cancer
Amasyalı AS, Kazan
E, Erol B. Bladder Cancer and Nos-no
Gene Polymorphısms. Journal of Nephrology Research 2015; 1(1): 25-29 Available from: URL:
http://www.ghrnet.org/index.php/jnr/article/view/1141
INTRODUCTION
Bladder cancer is one of the most common cancers in the world. This
cancer is the second most common malignancy of urinary tract cancer and fourth
most frequent cancer diagnosed in men accounting for 7% of total cancers and
the eighth most common cancer in women in the United States[1].
Bladder cancer is a multi-factorial disease that is mediated by both genetic
and environmental factors such as occupational chemical exposure, tobacco use,
some microorganisms and genetic factors[2].
Nitric oxide
(NO) is an important biological molecule with a variety of functions. Nitric
oxide synthase (NOS) is the responsible enzyme in NO production from
L-arginine. Three main isoforms, derived from separate genes, have been
described and named after the cells in which they were first found[3].
These are neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2) and
endothelial NOS (eNOS or NOS3)[4]. In the last three decades, the
role of NO in tumor cell biology and tumor angiogenesis has been firmly
established. NOS isoforms are reported to be present in human solid tumors and
tumor cell lines (Table 1). Importance of NOS gene polymorphisms relies on the
contradictory role of NO in carcinogenesis. At the present time, several
polymorphisms identified in human eNOS gene but a few variations are assumed to
have functional importance[5,6]. The G894T variation (rs1799983) may
alter eNOS activity or regulation. Several studies reported that some of the
eNOS gene polymorphisms are significantly associated with development of
several types of cancer[7,8].
NO has
multiple physiological functions, including vasodilatation, neuronal transmission,
smooth muscle relaxation and immunity and is released by endothelial cells[3,5].
The cellular effect of NO is complex and can be cytoprotective or cytotoxic,
depending on its concentration and cellular microenvironment[11]. At
low concentrations, NO may exert cytoprotective function through cell
homeostasis, muscle relaxation, neurotransmission and platelet function[4,12,13].
Low levels of NO may also protect endothelial cells from exposure to risk
factors such as reactive oxygen species (ROS) and tumor necrosis factor-a[14-16].
The specific actions whereby NO protects against ROS may include interacting
with metals to prevent the formation of oxygen species, scavenging oxidants,
preventing the degradation of metalloproteins and preventing lipid peroxidation[16].
At high concentrations, NO and its derivatives can cause DNA strand breaks and
impair the tumor suppressor function of p53, which may lead to carcinogenesis[17-20].
Nitric
oxide syntase
eNOS is one of three isoforms of NOS that generates NO in vascular
endothelium and is encoded by the eNOS gene which is localized to chromosome
7q35-36[21]. nNOS is located on chromosome 12 and iNOS on chromosome
17[22,23]. The eNOS gene have about 1,500 base pairs of upstream
promoter sequence similar to other NOS and include transcription factor-binding
sites that mediate regulation by estrogens, shear stres[24]. eNOS
generates low levels of the endogenous free radical nitric oxide during the
transformation of L-arginine to L-citrulline at the presence of
tetrahydrobiopterin (BH4), an essential eNOS cofactor[3,25]. It has
been shown that eNOS regulates blood pressure, platelet aggregation, leukocyte
adherence, and vascular smooth muscle cell mitogenesis and angiogenesis[26].
More than 168 polymorphisms have been identified in the eNOS gene[27].
Only three of these polymorphisms, namely 894G>T, intron 4a/b, and
-786T>C, seem to be functional, and they have been investigated for their
association with the risk of several diseases, predominantly cardiovascular
diseases[28,29]. Several polymorphisms in eNOS gene have been
identified, including a common missense variant at nucleotide position 894
(G894T) in exon 7, resulting in a substitution of glutamic acid to aspartic
acid at amino acid position 298. This polymorphism is associated with differing
susceptibility to cleavage in eNOS enzyme in transfected cells and human
endothelial cells, related to reduced basal NO production[30,31].
Previous studies have shown increased risk of coronary artery disease and
hypertension associated with eNOS Glu298Asp genotypes[32,33].
Nitric oxide
NO is a very important intercellular messenger molecule. However,
previous studies have indicated that NO may have both pro- and antitumor
functions, under varied conditions in the course of tumor initiation,
development, and progression[34,35] (Figure 1). The pro-tumor
property may be related to DNA damage, mutation of tumor suppressor gene p53,
promotion of angiogenesis and stimulation of tumor cell blood flow whereas the
antitumor effects may be associated with the induction of apoptosis, activation
of antioxidant defense, cytostatic effect and immunity[34,35]. The
effective NO functions depend, to a great extent, on its concentration, local
microenvironment and timing of production. Lancaster et al[11]
noted that heterogeneity in the chemical process, biological production of NO
and cellular responses to NO, among other factors, might render different
biological outcomes related to NO. Elevated levels of all three isoforms of
nitric oxide synthase have been found in human solid tumors, indicating that NO
is a mediator of tumor progression[36]. The production of NO is part
of the macrophages¡¯ antitumor immune response mechanism, yet an over-expression
of NO levels in tumor sites has been found to correlate with poor clinical
outcome[37]. Table 1 summarizes evidence in support of iNOS
association during tumor development in humans and animals[10].
Nitric
oxide syntase isoforms and polymorphisms
NOS isoforms
and polymorphisms are reported to be present in human solid tumors and tumor
cell lines[38]. Yang et al[4] did not observe a
significant relationship between NOS3 Glu298Asp and breast cancer risk, but we
did find that this polymorphism was associated with the risk of post-menopausal
breast cancer among subgroups of women defined by smoking status or intensity
of smoking. Ozturk et al[40] reported that Glu298Asp and VNTR
intron 4 polymorphisms in the eNOS gene could be an intriguing factor that
modulates an individual¡¯s risk of endometrial carcinoma in Turkish population.
Unal et al[41] showed that neither 984G>T nor intron 4a/b
polymorphisms were related with gastric cancer. Some studies have found that
NOS2A and NOS3 genetic polymorphisms are associated with prostate cancer risk[4,42].
Evidence for
NO involvement in tumour biology has been reported from several different forms
of cancer both in vitro and in vivo[43]. However,
there are conflicting reports whether NO promotes or inhibits tumour growth.
Thomae et al, described that low concentrations of NO stimulated
endothelial cell growth, whereas high concentrations acted in an inhibitory
fashion[45]. This dual effect of NO on cell growth has also been
demonstrated in bladder cancer cell lines by Morcos et al[46].
In a study, iNOS expression was found in biopsies from bladder tumours and they
found no correlation between the levels of iNOS and tumour grade or stage[9].
NO levels are higher in patients with CIS lesions than in patients with
papillary bladder tumours and this increase is also likely due to an elevated
expression of iNOS[9]. Furthermore, Several studies propose that NO
also actively mediate some of the anti tumour effects seen after BCG treatment[46,47].
NO levels are higher in the bladder after BCG treatment and are likely to
reflect an increased expression of iNOS in bladder urothelial cells and immune
competent cells in the submucosa and these findings are in line with previous
results implicating that BCG may act through NO/NOS pathways, which is further
supported that polymorphisms (eNOS -786T>C polymorphism, eNOS Glu298Asp
polymorphism) in the iNOS and eNOS genes may influence treatment outcome for BCG[9].
eNOS expression has been demonstrated in the endothelium of bladder tumour
vessels and endothelial derived NO, produced by eNOS, has been proposed to
promote angiogenesis and cancer invasiveness (48). In vitro studies on
bladder cancer cells have suggested a similar role for NO in bladder cancer,
promoting cell growth when produced at low concentrations whereas high
concentrations result in cytostatic and cytotoxic effects[46,47].
Increased iNOS
expression also has been found consistently in bladder cancers[49-52].
In one study, all 94 transitional cell carcinomas examined exhibited some
immunostaining for iNOS. All dysplastic lesions adjacent to carcinomas
exhibited staining patterns similar to malignant tissue, suggesting that
upregulation of iNOS is an early event during bladder carcinogenesis[49].
iNOS expression has been reported in several cancers including bladder cancer[48].
The iNOS (CCTTT)n promoter microsatellite polymorphism at -2.6 kb has been
suggested to be associated with gastric cancer and bladder cancer[53-55].
In a recent study by Ryk et al, a long set (13 or more) of (CCTTT)n
repeats were associated with a lower risk for developing bladder cancer but
also with a higher risk for disease progression and cancer specific death once
cancer had emerged[56]. In addition, eNOS polymorphisms have been
associated to cancer risk and progression[56]. Ryk et al, has
recently found a correlation between bladder cancer and both the eNOS promoter
polymorphism -786T>C and the intragenic eNOS polymorphism Glu298Asp[55].
iNOS promoter (-2.6 Kb) microsatellite (CCTTT)n polymorphism has been
correlated to the development and aggressiveness of bladder cancer, patients
with a long set of repeats of the (CCTTT)n polymorphism had a lower risk of
developing bladder cancer but a higher risk for stage progression and cancer
specific death once tumour had developed[55]. The presence of
elevated NO concentration and iNOS expression in the urinary bladder from BCG
treated patients and patients with CIS further supports the notion that NO may
be an important factor in bladder cancer biology and that the BCG effect on
superficial bladder cancer may partly be due to stimulation of local NO
formation[57].
Ryk et al
reported that the eNOS is expressed in the bladder tumor vessels, suggesting
the possible relation between eNOS and the bladder cancer. They found no
increased risk of bladder cancer with Glu298Asp polymorphism. However there was
an association between the Glu298Asp and bladder tumor grade[5]. In
a study by Verim et alsuggested an increased risk role of eNOS GT genotype in
bladder cancer susceptibility in our Turkish population[58]. Koskela
et al reported that the iNOS is found to be localized to the urothelium
and macrophages underlying it and their study also confirms elevated levels of
endogenously formed NO and increased mRNA expression and protein levels for
iNOS in patients with BCG treated bladder cancer[59]. In vivo
studies results provide evidence for frequent iNOS protein expression in TCC.
In addition, Their observations indicate that overexpression of iNOS expression
may be one of the early events in the carcinogenesis of TCC[50].
Some results suggest that various urinary bladder lesions alter the normal
differentiation pathway of urothelial superficial cells, which induces the
expression of NOS in mitochondria of partially differentiated cells[60-61].
Recently
published study showed a strong relationship between the eNOS4a/b polymorphism
and superficial bladder cancer. Univariate analyses revealed that the eNOS4a/b
polymorphism predicted recurrence and progression. The authors suggested that a
genotype containing the ¡¯a¡¯ allele of the eNOS4a/b polymorphism may be a risk
factor for bladder cancer. Furthermore, patients harboring the ¡®aa¡¯ plus ¡®ab¡¯
genotype are more likely to experience tumor recurrence and progression. In
addition, compared to patients with the ¡®b¡¯ allele, those with the eNOS4a/b
gene polymorphism ¡®a¡¯ allele or at least 1 mutated ¡®a¡¯ allele (aa or ab) were
more susceptible to high grade disease (p=0.007) and bladder tumor
invasiveness[62].
Conclusion
Nitric oxide (NO) is an important biological molecule with a variety of
functions. NO may have both pro- and antitumor functions. NO could take part in
tumour development and progression. However, for researchers, the problems of
NO chemistry in the tumor environment, NO output, NO protumor activity, and the
target cell type remain to be further investigated by moving from in vitro
biology to more relevant animal models. NOS select inhibitors and their
possible use for the prevention and treatment of various cancers. NO may be
involved in the anti-tumor mechanism that BCG exerts on bladder cancer cells.
CONFLICT OF INTERESTS
The authors declare no conflict of interest.
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Peer reviewer:s Monica C. Botelho,
PhD, Department of Health Promotion and Chronic Diseases, National Institute of
Health Dr. Ricardo Jorge, Rua Alexandre Herculano, 321, 4000-055 Porto,
Portugal; Mohammad Ali Mohammad, Prof Medical Biochemistry and Molecular
Biology, Cancer Biology Dept., National Cancer Institute, Foum Al Khalieg,
Cairo, Egypt.
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