Research IndicatorsGraph generated 28 February 2015 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: NOS3 (cancer-related)
Angiotensinogen (AGT), the precursor of angiotensin I, is known to be involved in tumor angiogenesis and associated with the pathogenesis of coronary atherosclerosis. This study was undertaken to determine the role played by AGT in endothelial progenitor cells (EPCs) in tumor progression and metastasis. It was found that the number of EPC colonies formed by AGT heterozygous knockout (AGT(+/-)) cells was less than that formed by wild-type (WT) cells, and that the migration and tube formation abilities of AGT(+/-) EPCs were significantly lower than those of WT EPCs. In addition, the gene expressions of vascular endothelial growth factor (VEGF), Flk1, angiopoietin (Ang)-1, Ang-2, Tie-2, stromal derived factor (SDF)-1, C-X-C chemokine receptor type 4 (CXCR4), and of endothelial nitric oxide synthase (eNOS) were suppressed in AGT(+/-) EPCs. Furthermore, the expressions of hypoxia-inducible factor (HIF)-1α and -2α were downregulated in AGT(+/-) early EPCs under hypoxic conditions, suggesting a blunting of response to hypoxia. Moreover, the activation of Akt/eNOS signaling pathways induced by VEGF, epithelial growth factor (EGF), or SDF-1α were suppressed in AGT(+/-) EPCs. In AGT(+/-) mice, the incorporation of EPCs into the tumor vasculature was significantly reduced, and lung tumor growth and melanoma metastasis were attenuated. In conclusion, AGT is required for hypoxia-induced vasculogenesis.
Chen Y, Li J, Guo Y, Guo XYNitric oxide synthase 3 gene variants and colorectal cancer: a meta-analysis.
Asian Pac J Cancer Prev. 2014; 15(8):3811-5 [PubMed
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BACKGROUND: Colorectal cancer (CRC) is the worldwide disease which causes enormous losses every year. Recent studies suggested that environmental and gene factors might be the etiologies in increasing the risk of morbidity. Nitric oxide synthase 3 (NOS3) gene polymorphisms are said to be associated with CRC risk but the conclusion is still controversial.
MATERIALS AND METHODS: Pubmed and HuGENet databases up to December 2013 were used in this meta-analysis. Three different certain genotypic models were applied, namely dominant (AA+AC versus CC), recessive (AA versus AC+CC), per-allele analysis (A vs C). In addition, information on tumor sites and pathologic stages was collected. The strength of associations was assessed through combining odds ratio (OR) and 95% confidence interval (CI).
RESULTS: Finally, five and three studies about the rs1799983 and rs2070744 were covered in the analysis with 2,745 cases and 2,478 controls. Three models were applied, but no significant association was found for NOS3 G894T/rs1799983 (dominant: OR=0.999, 95%CI=0.797-1.253, I2=63.8%; recessive: OR=0.924, 95%CI=0.589-1.450, I2=59.3%; allele analysis: OR=0.979, 95%CI=0.788-1.216, I2=74.9%) and T-786C/rs2070744 (dominant: OR=1.138, 95%CI=0.846-1.530, I2=67.9%; recessive: OR=0.956, 95%CI=0.708-1.291, I2=0.0%; allele analysis: OR=1.110, 95%CI=0.865-1.425, I2=69.4%). The same results were also obtained for tumor sites and pathologic stage subgroups. After further analyzing the NOS3 gene, rs1799983 as the tag- and functional SNP was presented.
CONCLUSIONS: On the basis of this meta-analysis and the characteristics of the NOS3 gene, we suggested rs1799983 might be a key locus associated with CRC risk. Further prospective studies were needed to make more comprehensive explanation of the associations.
Wu JH, Yang K, Ma HS, Xu YAssociation of endothelia nitric oxide synthase gene rs1799983 polymorphism with susceptibility to prostate cancer: a meta-analysis.
Tumour Biol. 2014; 35(7):7057-62 [PubMed
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Genetic polymorphism of endothelial nitric oxide synthase (NOS3) rs1799983 (Glu298Asp) has been implicated to alter the risk of prostate cancer, but the results are controversial. Two investigators independently searched the PubMed, Cochrane Library, and Embase electronic databases up to September 30, 2013. Summary odds ratios (OR) and 95 % confidence interval (CI) for rs1799983 polymorphism and prostate cancer were calculated. Statistical analysis was performed with the software program Review Manage, version 5.0 and Stata 11.0. A total of 7 independent studies, including 1,792 cases and 2,411 controls, were identified. Our analysis suggested that rs1799983 was associated with prostate cancer risk in overall population under dominant model (OR = 1.15, 95%CI = 1.01-1.30, P = 0.03) and allelic model (OR = 1.11, 95%CI = 1.00-1.22, P = 0.04). In the subgroup analysis, we detected no association between rs1799983 polymorphism and prostate risk in Caucasian population under all the genetic models. This meta-analysis showed the evidence that NOS3 rs1799983 polymorphism was associated with a risk of prostate cancer development in overall populations.
He H, Xu YJ, Yin JY, et al.Association of nitric oxide synthase 3 (NOS3) 894 G>T polymorphism with prognostic outcomes of anthracycline in Chinese patients with acute myeloid leukaemia.
Clin Exp Pharmacol Physiol. 2014; 41(6):400-7 [PubMed
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The aim of the present study was to investigate the influence of the nitric oxide synthase 3 (NOS3) 894 G>T polymorphism on prognostic outcomes of anthracycline in Chinese patients with de novo intermediate-risk acute myeloid leukaemia (AML) and to examine the gene expression level in relation to genetic variation. In all, 225 Chinese patients with intermediate-risk AML (at the complete remission stage) treated with anthracycline were enrolled in the study. The 894 G>T polymorphism of the NOS3 gene was analysed by allele-specific matrix-assisted laser desorption ionization time-of-flight. Expression of NOS3 mRNA was tested in 72 patients of known genotype for NOS3 894 G>T. The clinical characteristics of these patients were obtained from medical records. Survival analysis showed that patients with AML (GG genotype) had a longer overall survival (OS; P = 0.006). After adjusting for age, gender, leucocyte count, haemoglobin level, platelet level, French, American and Britain (FAB) classification, lactate dehydrogenase levels, Eastern Cooperative Oncology Group Performance Status, nucleophosmin gene and fms-related tyrosine kinase 3 gene, multivariate survival analysis showed that the NOS3 894 G>T polymorphism appeared to be a predicting factor for OS (P = 0.014; hazard ratio = 1.856). However, no significant associations between the NOS3 894 G>T polymorphism and relapse-free survival and relapse in patients with AML were observed. Gene expression levels were significantly higher in patients with the GG genotype than in patients with the GT and TT genotypes (P = 0.033). The findings suggest that the NOS3 894 G>T variant may be a biomarker for the prediction of OS in Chinese patients with AML.
Zhang Y, Jia Q, He Q, et al.The Glu298Asp polymorphism in the NOS3 gene and the risk of prostate cancer.
Tumour Biol. 2014; 35(5):4735-9 [PubMed
] Related Publications
The Glu298Asp polymorphism in the NOS3 gene has been implicated as a risk factor for prostate cancer. To date, several studies have evaluated the associations between the Glu298Asp polymorphism and prostate cancer risk; however, the results were inconclusive. The aim of the current study was to perform a meta-analysis to investigate the association between the polymorphism and the risk of prostate cancer. A total of 3,206 cases and 3,880 controls from eight case-control studies were included for data synthesis. The overall results suggested no significant association between the polymorphism and the risk of prostate cancer (OR=1.01, 95% CI=0.92-1.11, p = 0.83 for Asp/Asp+Glu/Asp vs. Glu/Glu). In the stratified analysis according to ethnicity, no significant associations were observed in Asians and Europeans. The current meta-analysis suggested that the Glu298Asp polymorphism of the NOS3 gene might not contribute to the risk of prostate cancer.
Gao QG, Chan HY, Man CW, Wong MSDifferential ERα-mediated rapid estrogenic actions of ginsenoside Rg1 and estren in human breast cancer MCF-7 cells.
J Steroid Biochem Mol Biol. 2014; 141:104-12 [PubMed
] Related Publications
Recent studies indicated that both estren and Rg1 appear to be able to activate mitogen-activated protein kinase (MAPK) pathway in estrogen responsive cells. Rg1 could lead to MAPK activation through ligand-independent activation of estrogen receptor (ER), while estren could activate the Src-MAPK pathway in an ERE-independent manner. Thus, it is important to understand the mechanistic insights on the difference in transcriptional activation between estren and Rg1. The present study also addressed the differential abilities of Rg1 and estren in terms of the ability to activate ER and the ability to induce ER translocation in MCF-7 cells. Our data indicated that Rg1 could increase pS2 gene expression, and could recruit the co-activator steroid receptor co-activator-1 (SRC-1) to the pS2 promoter. Rg1 could also induce ERα nuclear translocation as well as ERα phosphorylation at Ser118 principally in the cytoplasm in MCF-7 cells. We deduced that estren induced ERE-dependent transcriptional activity and activated ERα at Ser118 occurred in the nucleus of MCF-7 cells. However, it was found to decrease pS2 gene expression and failed to induce the recruitment of SRC-1 to the pS2 promoter in MCF-7 cells. Our results suggest that the abilities of Rg1 and estren to regulate pS2 gene expression, to recruit co-activators as well as to induce sub-cellular distribution of ERα are dramatically different.
α-solanine, a steroidal glycoalkaloid in potato, was found to have proliferation-inhibiting and apoptosis-promoting effect on multiple cancer cells, such as clone, liver, melanoma cancer cells. However, the antitumor efficacy of α-solanine on pancreatic cancer has not been fully evaluated. In this study, we inquired into the anti-carcinogenic effect of α-solanine against human pancreatic cancer cells. In the present study, we investigated the anti-carcinogenic effect of α-solanine against human pancreatic cancer cells. In vitro, α-solanine inhibited proliferation of PANC-1, sw1990, MIA PaCa-2 cells in a dose-dependent manner, as well as cell migration and invasion with atoxic doses. The expression of MMP-2/9, extracellular inducer of matrix metalloproteinase (EMMPRIN), CD44, eNOS and E-cadherin were suppressed by α-solanine in PANC-1 cells. Moreover, significantly decreased vascular endothelial growth factor (VEGF) expression and tube formation of endothelial cells were discerned following α-solanine treatment. Suppressed phosphorylation of Akt, mTOR, and Stat3, and strengthen phosphorylation of β-catenin was found, along with markedly decreased tran-nuclear of NF-κB, β-catenin and TCF-1. Following the administration of α-solanine (6 µg/g for 2 weeks) in xenograft model, tumor volume and weight were decreased by 61% and 43% (p<0.05) respectively, showing decreased MMP-2/9, PCNA and VEGF expression. In conclusion, α-solanine showed beneficial effects on pancreatic cancer in vitro and in vivo, which may via suppressing the pathway proliferation, angiogenesis and metastasis.
Zhang Y, Jia Q, Xue P, et al.The -786T > C polymorphism in the NOS3 gene is associated with increased cancer risk.
Tumour Biol. 2014; 35(4):3535-40 [PubMed
] Related Publications
The -786T > C polymorphism in NOS3 gene may affect the DNA repair pathways and be associated with risk of cancer. However, the results of previous studies are inconsistent. The objective of this study is to investigate the association between the -786T > C polymorphism in NOS3 and risk of cancer by meta-analysis. We searched PubMed, Embase, CNKI, and Wanfang databases and the last search was updated on Sept. 20, 2013. Statistical analysis was performed using Revman4.2 and Stata10.0 software. A total of 9 case-control studies concerning 4,089 cases and 3,847 controls were included. The results suggested a significant association between the -786T > C polymorphism in NOS3 and cancer risk (CC vs. TT + CT; OR = 1.30, 95% CI = 1.07-1.57, P = 0.007) in total analysis. In the subgroup analysis by ethnicity and cancer types, significant associations were found in the breast cancer subgroup (OR 1.51, 95% CI 1.07-2.12; P = 0.02) and European subgroup (OR 1.26, 95% CI 1.01-1.58; P = 0.04). The current meta-analysis suggested that the -786T > C polymorphisms in NOS3 may be a risk factor for cancer. In the future, more case-control studies are needed to validate our results.
Cao Y, Lupo PJ, Swartz MD, et al.Using a Bayesian hierarchical model for identifying single nucleotide polymorphisms associated with childhood acute lymphoblastic leukemia risk in case-parent triads.
PLoS One. 2013; 8(12):e84658 [PubMed
] Free Access to Full Article Related Publications
Childhood acute lymphoblastic leukemia (ALL) is a condition that arises from complex etiologies. The absence of consistent environmental risk factors and the presence of modest familial associations suggest ALL is a complex trait with an underlying genetic component. The identification of genetic factors associated with disease is complicated by complex genetic covariance structures and multiple testing issues. Both issues can be resolved with appropriate Bayesian variable selection methods. The present study was undertaken to extend our hierarchical Bayesian model for case-parent triads to incorporate single nucleotide polymorphisms (SNPs) and incorporate the biological grouping of SNPs within genes. Based on previous evidence that genetic variation in the folate metabolic pathway influences ALL risk, we evaluated 128 tagging SNPs in 16 folate metabolic genes among 118 ALL case-parent triads recruited from the Texas Children's Cancer Center (Houston, TX) between 2003 and 2010. We used stochastic search gene suggestion (SSGS) in hierarchical Bayesian models to evaluate the association between folate metabolic SNPs and ALL. Using Bayes factors among these variants in childhood ALL case-parent triads, two SNPs were identified with a Bayes factor greater than 1. There was evidence that the minor alleles of NOS3 rs3918186 (OR = 2.16; 95% CI: 1.51-3.15) and SLC19A1 rs1051266 (OR = 2.07; 95% CI: 1.25-3.46) were positively associated with childhood ALL. Our findings are suggestive of the role of inherited genetic variation in the folate metabolic pathway on childhood ALL risk, and they also suggest the utility of Bayesian variable selection methods in the context of case-parent triads for evaluating the role of SNPs on disease risk.
Ramírez-Patiño R, Figuera LE, Puebla-Pérez AM, et al.Intron 4 VNTR (4a/b) polymorphism of the endothelial nitric oxide synthase gene is associated with breast cancer in Mexican women.
J Korean Med Sci. 2013; 28(11):1587-94 [PubMed
] Free Access to Full Article Related Publications
The endothelial nitric oxide synthase (eNOS) gene plays an important role in several biological functions. Polymorphisms of the eNOS gene have been associated with cancer. It has been suggested that the VNTR 4 a/b polymorphism may affect the expression of eNOS and contributes to tumor promotion in the mammary gland. We examined the role of the eNOS4 a/b polymorphism by comparing the genotypes of 281 healthy Mexican women with the genotypes of 429 Mexican women with breast cancer (BC). The observed genotype frequencies for control and BC patients were 0.6% and 0.7% for a/a (polymorphic); 87% and 77% for a/a (wild type); and 12% and 22% for a/b respectively. We found that the odds ratio (OR) was 1.9, with a 95% confidence interval (95%CI) of 1.29-2.95, P = 0.001 for genotypes a/a-a/b, b/c. The association was also evident when comparing the distribution of the a/a-a/b genotypes in patients with high levels of glutamate-oxaloacetate transaminase (SGOT) (OR, 1.93; 95% CI, 1.14-3.28; P = 0.015); undergoing menopause with high levels of SGOT (OR, 2.0; 95% CI, 1.1-3.84); and with high levels of glutamic-pyruvic transaminase (SGPT) (OR, 3.5; 95% CI, 1.56-8.22). The genotypes a/a-a/b are associated with BC susceptibility in the analyzed samples from the Mexican population.
Belgorosky D, Langle Y, Prack Mc Cormick B, et al.Inhibition of nitric oxide is a good therapeutic target for bladder tumors that express iNOS.
Nitric Oxide. 2014; 36:11-8 [PubMed
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Bladder cancer is the second cause of death for urological tumors in man. When the tumor is nonmuscle invasive, transurethral resection is curative. On the other hand, radical cystectomy is the treatment chosen for patients with invasive tumors, but still under treatment, these patients have high risk of dying, by the development of metastatic disease within 5 years. It is therefore important to identify a new therapeutic target to avoid tumor recurrences and tumor progression. Nitric oxide (NO) is an important biological messenger known to influence several types of cancers. In bladder cancer, production of NO and expression and activity of inducible NO synthase was associated to recurrence and progression. The objective of this work was to analyze if inhibition of nitric oxide production could be considered a therapeutic target for bladder tumors expressing iNOS. Using a bladder cancer murine model with different invasiveness grade we have demonstrated that NO inhibition was able to inhibit growth of bladder tumors expressing iNOS. Furthermore, invasive properties of MB49-I orthotopic growth was inhibited using NO inhibitors. This paper also shows that levels of NO in urine can be correlated with tumor size. In conclusion, inhibition of NO could be considered as a therapeutic target that prevents tumor growth and progression. Also, urine NO levels may be useful for measuring tumor growth.
Genome-wide association studies (GWAS) have identified over 46 SNPs associated with human prostate cancer (PCa). Some studies have shown correlation of the nitric oxide synthase (NOS) NOS3 gene polymorphisms with the risk and/or progression of PCa. This study aimed to evaluate the association of NOS3 gene polymorphisms (-786T>C, -764A>G, -714G>T, -690C>T, -649G>A and 894G>T) with PCa risk and progression. 150 patients with PCa, 150 patients with BPH and 100 age-matched healthy controls were recruited in this study. Genotyping of promoter polymorphisms was performed by bi-directional DNA sequencing, and for 894G>T by RFLP analysis. There was no significant association between the alleles and genotypes of these genetic variants and PCa risk. For -786T>C polymorphism, we found that C allele is associated with absence of metastases, assuming dominant genetic model (P = 0.049; OR, 0.50; 95% CI, 0.25-1.00). It was found that, compared with NOS3 -690C>T variant CC genotype, CT and TT genotypes confer decreased risk of developing metastases (dominant model, P = 0.015, OR, 0.24; 95% CI, 0.07-0.88) and show association with low clinical tumour stage, compared with stages T3 and T4 (dominant model, P = 0.046, OR, 0.20; 95% CI, 0.04-1.02). Genetic variants -764A>G, -714G>T, -649G>A were not detected in our study group. There is evidence of an inverse correlation of the NOS3 894G>T minor allele with high serum PSA (>20 ng/ml) (dominant model, P = 0.013, OR, 0.37; 95% CI, 0.17-0.82). Our results suggest that NOS3 gene polymorphisms are genetic susceptibility factors for the progression of PCa and patient outcome.
Kumazoe M, Kim Y, Bae J, et al.Phosphodiesterase 5 inhibitor acts as a potent agent sensitizing acute myeloid leukemia cells to 67-kDa laminin receptor-dependent apoptosis.
FEBS Lett. 2013; 587(18):3052-7 [PubMed
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(-)-Epigallocatechin-3-O-gallate (EGCG), a polyphenol in green tea, induces apoptosis in acute myeloid leukemia (AML) cells without affecting normal cells. In this study, we observed that cGMP acts as a cell death mediator of the EGCG-induced anti-AML effect through acid sphingomyelinase activation. EGCG activated the Akt/eNOS axis, a well-known mechanism in vascular cGMP upregulation. We also observed that a major cGMP negative regulator, phosphodiesterase 5, was overexpressed in AML cells, and PDE5 inhibitor, an anti-erectile dysfunction drug, synergistically enhanced the anti-AML effect of EGCG. This combination regimen killed AML cells via overexpressed 67-kDa laminin receptors.
Labruijere S, van Houten EL, de Vries R, et al.Analysis of the vascular responses in a murine model of polycystic ovary syndrome.
J Endocrinol. 2013; 218(2):205-13 [PubMed
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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of there productive age, but the exact pathophysiological mechanisms involved remain unclear. Cardiovascular disease risk is increased in PCOS patients and endothelial damage has been observed. We recently developed a mouse model of PCOS with reproductive and metabolic characteristics resembling those observed in women with PCOS. In this model we studied vascular function with particular emphasis on markers of vascular endothelial function. Animals were treated for 90 days with dihydrotestosterone (DHT; 27.5 mg/day) or placebo using subcutaneous continuous-release pellets. Aortas were isolated for isometric force recordings in organ baths to investigate endothelial and vascular smooth muscle characteristics. Lungs were used to analyze endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Asymmetric dimethylarginine (ADMA) levels were investigated in serum to assess endothelial damage. Expression of androgen receptor (Ar) mRNA was studied in aortas. DHT treatment (compared with placebo) induced i) a significant decrease in acetylcholine-induced aortic relaxations, with no change in calcitonin gene related peptide- or sodium nitroprusside-induced relaxations, as well as 5-hydroxytryptamine-induced contractions; ii) no change in eNOS expression/phosphorylation in lungs or in plasma ADMA levels; and iii) a twofold increase in aortic AR expression. Our results suggest that, in DHT-exposed mice, hyperandrogenemia specifically decreases endothelium dependent vasorelaxation without deterioration of smooth muscle function. This study may initiate further investigations to elucidate underlying mechanism for the phenotype that is present in these animals, as well as in PCOS patients.
In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5' domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa.
Dan S, Bai L, Li-Jie W, et al.Pharmacogenetic angiogenesis profiling for first-line chemotherapy in patients with advanced gastric cancer.
Cancer Invest. 2013; 31(6):390-6 [PubMed
] Related Publications
We retrospectively investigated germline polymorphisms in angiogenesis pathway genes (14 SNPs) and their correlation to clinical outcome (progression free survival and overall survival) in 128 patients with unresectable-advanced gastric carcinoma (AGC) treated with first-line chemotherapy. Our analysis revealed that Endostatin +4349 G>A polymorphism exhibited a worse progression free survival (PFS) and overall survival (OS) compared with the GG genotype. Significant OS difference was also observed in the endothelial nitric oxide synthase (eNOS)-786 T>C polymorphism. Hence, common germline variants in Endostatin and eNOS genes have predictive significance for clinical outcome and survivality in AGC patients treated with first-line chemotherapy.
Verim L, Toptas B, Ozkan NE, et al.Possible relation between the NOS3 gene GLU298ASP polymorphism and bladder cancer in Turkey.
Asian Pac J Cancer Prev. 2013; 14(2):665-8 [PubMed
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Endothelial nitric oxide synthase (eNOS), encoded by the NOS3 gene, has been suggested to play an important role in uncontrolled cell growth in several cancer types. The objective of this study was to evaluate the role of the NOS3 Glu298Asp polymorphism in bladder cancer susceptibility in a Turkish population. We determined the genotypes of 66 bladder cancer cases and 88 healthy controls. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. A significant association for NOS3 Glu298Asp heterozygotes genotypes and T allely were found between healthy controls and bladder cancer, respectively (p<0.001: p=0.002). There were no significant associations between any genotypes and the stage, grade, and histological type of bladder cancer. Our study suggested an increased risk role of NOS3 GT genotype in bladder cancer susceptibility in our Turkish population.
Marcoux S, Robaey P, Gahier A, et al.Role of NOS3 DNA variants in externalizing behavioral problems observed in childhood leukemia survivors.
J Pediatr Hematol Oncol. 2013; 35(4):e157-62 [PubMed
] Related Publications
OBJECTIVE: Neuropsychological problems occurrence varies among childhood cancer survivors, and associated risk factors have not been fully deciphered. We wanted to study the role of genetic variants in behavioral problems in this population.
STUDY DESIGN: Behavioral problems in pediatric acute lymphoblastic leukemia patients (n=138) were investigated longitudinally, using the Child Behavior Checklist questionnaire and multilevel statistical modeling. Thirty-four candidate polymorphisms, related to anticancer drug effects, were investigated.
RESULTS: NOS3 gene functional polymorphisms showed significant association: patients homozygous for the minor allele at investigated loci showed decreased externalizing behavioral problems scores over time (t tests: T-786C n=69, P=0.003; G894T n=71, P=0.065). The effect was even more pronounced for individuals that are homozygous for the -786C844T haplotype (t test, n=69, P<0.001) and results were supported by multilevel modeling analyses (P<0.001). No such association was observed for internalizing behavioral problems.
CONCLUSION: NOS3 variants modulate externalizing problems individual trajectories, likely in relationship with glucocorticoid exposure.
Growing evidence suggests that the angiotensin-converting enzyme (ACE) and endothelial nitric oxide synthase (eNOS) genes are associated with risk in a wide range of cancers. The objective of this study was to examine whether two DNA polymorphisms at the ACE insertion/deletion (I/D) and the variable number of tandem repeats in NOS intron 4 (4a/4b) were linked to the risk of developing hepatocellular carcinoma (HCC) in a Chinese population. The polymorphisms at ACE I/D and eNOS 4a/4b were genotyped in 293 HCC patients and 384 healthy control subjects using polymerase chain reaction. The frequencies of the D allele (p=0.003, OR=0.72, 95% CI=0.58-0.90) in the ACE gene of HCC patients were significantly different from the healthy controls, and a significantly decreased HCC risk was associated with the DD genotype in both the recessive (p<0.001, OR=0.19, 95% CI=0.11-0.34) and codominant models (p<0.001, OR=0.26, 95% CI=0.14-0.48). This study provided evidence that the ACE I/D polymorphism is associated with HCC, indicating that the ACE I/D polymorphism contributes to HCC progression in the Chinese population.
Seibold P, Hall P, Schoof N, et al.Polymorphisms in oxidative stress-related genes and mortality in breast cancer patients--potential differential effects by radiotherapy?
Breast. 2013; 22(5):817-23 [PubMed
] Related Publications
We assessed whether variants in 22 oxidative stress-related genes are associated with mortality of breast cancer patients and whether the associations differ according to radiotherapy. Using a prospective cohort of 1348 postmenopausal breast cancer patients, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for 109 single nucleotide polymorphisms (SNPs) using Cox proportional hazards regression. Validation of results was attempted using two Scandinavian studies. Eleven SNPs in MT2A, NFE2L2, NQO1, PRDX1, and PRDX6 were significantly associated with overall mortality after a median follow-up of 5.7 years. Three SNPs in NQO1 (rs2917667) and in PRDX6 (rs7314, rs4916362) were consistently associated with increased risk of dying across all three study populations (pooled: HRNQO1_rs2917667 1.20, 95% CI 1.00-1.44, p = 0.051; HRPRDX6_rs7314 1.16, 95% CI 1.00-1.35, p = 0.056, HRPRDX6_rs4916362 1.14 95% CI 1.00-1.32, p = 0.062). Potential effect modification by radiotherapy was found for CAT_rs769218. In conclusion, genetic variants in NQO1 and PRDX6 may modify breast cancer prognosis.
BACKGROUND: Heterogeneously distributed hypoxic areas are a characteristic property of locally advanced breast cancers (BCa) and generally associated with therapeutic resistance, metastases, and poor patient survival. About 50% of locally advanced BCa, where radiotherapy is less effective are suggested to be due to hypoxic regions. In this study, we investigated the potential of bioactive phytochemicals in radio-sensitizing hypoxic BCa cells.
METHODS: Hypoxic (O2-2.5%; N2-92.5%; CO2-5%) MCF-7 cells were exposed to 4 Gy radiation (IR) alone or after pretreatment with Curcumin (CUR), curcumin analog EF24, neem leaf extract (NLE), Genistein (GEN), Resveratrol (RES) or raspberry extract (RSE). The cells were examined for inhibition of NFκB activity, transcriptional modulation of 88 NFκB signaling pathway genes, activation and cellular localization of radio-responsive NFκB related mediators, eNos, Erk1/2, SOD2, Akt1/2/3, p50, p65, pIκBα, TNFα, Birc-1, -2, -5 and associated induction of cell death.
RESULTS: EMSA revealed that cells exposed to phytochemicals showed complete suppression of IR-induced NFκB. Relatively, cells exposed EF24 revealed a robust inhibition of IR-induced NFκB. QPCR profiling showed induced expression of 53 NFκB signaling pathway genes after IR. Conversely, 53, 50, 53, 53, 53 and 53 of IR-induced genes were inhibited with EF24, NLE, CUR, GEN, RES and RSE respectively. In addition, 25, 29, 24, 16, 11 and 21 of 35 IR-suppressed genes were further inhibited with EF24, NLE, CUR, GEN, RES and RSE respectively. Immunoblotting revealed a significant attenuating effect of IR-modulated radio-responsive eNos, Erk1/2, SOD2, Akt1/2/3, p50, p65, pIκBα, TNFα, Birc-1, -2 and -5 with EF24, NLE, CUR, GEN, RES or RSE. Annexin V-FITC staining showed a consistent and significant induction of IR-induced cell death with these phytochemicals. Notably, EF24 robustly conferred IR-induced cell death.
CONCLUSIONS: Together, these data identifies the potential hypoxic cell radio-sensitizers and further implies that the induced radio-sensitization may be exerted by selectively targeting IR-induced NFκB signaling.
Predictive biomarkers are needed to triage patients to the best therapy. We prospectively planned examination of sequential blood, biopsy, and functional imaging with which to confirm the mechanism and to identify potential predictive biomarkers in a phase Ib clinical trial expansion of patients with solid tumors receiving sorafenib/bevacizumab. The maximally tolerated doses of sorafenib at 200 mg twice daily with bevacizumab at 5 mg/kg every other week were given to biopsiable patients. Patients were randomized to receive either sorafenib or bevacizumab monotherapy for the first 28-day cycle with the second drug added with cycle 2. Biopsies, dynamic contrast-enhanced MRI, and fluorodeoxyglucose-proton emission tomography were done pre-therapy and at 2 and 6 weeks (2 weeks into combination therapy). Tumor and serum proteomics, Ras/Raf mutational analysis, and functional imaging results were examined individually and across the dataset to identify potential changes predictive of response to therapy and those that confirm the biochemical drug mechanism(s). Therapy with sorafenib/bevacizumab resulted in clinical benefit in 45% of this mixed solid tumor group. ERK activation and microvessel density were decreased with monotherapy treatment with sorafenib or bevacizumab, respectively; whereas a decreased signal over the group of total AKT, phospho(p)-VEGF receptor2, p-endothelial nitric-oxide synthase, b-RAF, and cleaved poly(ADP-ribose) polymerase was associated with earlier progression of disease. Tumor metabolic activity decreased in those patients with clinical benefits lasting longer than 4 months, and activity increased with progression of disease. Cleavage of caspase 3 and poly(ADP-ribose) polymerase was increased, and Ki67 expression decreased in patients with prolonged clinical benefits, consistent with decreased proliferation and increased apoptosis. The conglomerate analysis, incorporating pharmacodynamic and tumor biochemistry, demonstrated sorafenib/bevacizumab-targeted vascular activity in the tumor. Results suggest potential biomarkers for which changes, as a group, during early therapeutic exposure may predict clinical benefit.
Jungbauer A, Medjakovic SPhytoestrogens and the metabolic syndrome.
J Steroid Biochem Mol Biol. 2014; 139:277-89 [PubMed
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Phytoestrogens are a diverse class of non-steroidal compounds that have an affinity for estrogen receptors α and β, for the peroxisome proliferator-activated receptor (PPAR) family and for the aryl hydrocarbon receptor. Examples of phytoestrogens include prenylated flavonoids, isoflavones, coumestans and lignans. Many phytoestrogens counteract the cellular derailments that are responsible for the development of metabolic syndrome. Here we propose a mechanism of action which is based on five pillars/principles. First, phytoestrogens are involved in the downregulation of pro-inflammatory cytokines, such as COX-2 and iNOS, by activating PPAR and by inhibiting IκB activation. Second, they increase reverse cholesterol transport, which is mediated by PPARγ. Third, phytoestrogens increase insulin sensitivity, which is mediated via PPARα. Fourth, they exert antioxidant effects by activating antioxidant genes through KEAP. Fifth, phytoestrogens increase energy expenditure by affecting AMP-activated kinase signaling cascades, which are responsible for the inhibition of adipogenesis. In addition to these effects, which have been demonstrated in vivo and in clinical trials, other effects, such as eNOS activation, may also be important. Some plant extracts from soy, red clover or licorice can be described as panPPAR activators. Fetal programming for metabolic syndrome has been hypothesized; thus, the consumption of dietary phytoestrogens during pregnancy may be relevant. Extracts from soy, red clover or licorice oil have potential as plant-derived medicines that could be used to treat polycystic ovary syndrome, a disease linked to hyperandrogenism and obesity, although clinical trials have not yet been conducted. Phytoestrogens may help prevent metabolic syndrome, although intervention studies will be always be ambiguous, because physical activity and reduced calorie consumption also have a significant impact. Nevertheless, extracts rich in phytoestrogens may be an alternative treatment or may complement conventional treatment for diseases linked with metabolic syndrome. This article is part of a Special Issue entitled 'Phytoestrogens'.
Jang MJ, Jeon YJ, Kim JW, et al.Association of eNOS polymorphisms (-786T>C, 4a4b, 894G>T) with colorectal cancer susceptibility in the Korean population.
Gene. 2013; 512(2):275-81 [PubMed
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BACKGROUND: Polymorphisms of endothelial nitric oxide synthases (eNOS) have been shown to be associated with cancer susceptibility. However, the results of such studies are conflicting to date. We investigated whether polymorphisms of the eNOS gene correlated with patients with colorectal cancer (CRC), relative to healthy individuals.
PATIENTS AND METHODS: In the present study, we analyzed three polymorphisms of eNOS (-786T>C, 4a4b, and 894G>T) in 509 healthy controls and 528 patients with CRC. The genotyping of eNOS polymorphisms was performed using polymerase chain reaction or polymerase chain reaction-restriction fragment length polymorphism assays.
RESULTS: We found that the TC+CC genotype of the -786T>C polymorphism was significantly associated with an increased risk of CRC compared with the TT genotype. Similarly, the GT+TT genotype of the 894G>T polymorphism was associated with an increased susceptibility to CRC. However, no evidence was found for any association between the 4a4b polymorphism and CRC risk. In addition, the C/4b/G (-786T>C/4a4b/894G>T) haplotype was significantly associated with increased risk of CRC and C/4b/T (-786T>C/4a4b/894G>T) haplotype was only detected in CRC patients.
CONCLUSIONS: Our study suggests that the eNOS -786T>C and 894G>T polymorphisms may be associated with the development of CRC in the Korean population.
Amasyali AS, Kucukgergin C, Erdem S, et al.Nitric oxide synthase (eNOS4a/b) gene polymorphism is associated with tumor recurrence and progression in superficial bladder cancer cases.
J Urol. 2012; 188(6):2398-403 [PubMed
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PURPOSE: We investigated the relationship between the distribution of the eNOS4a/b polymorphism and the clinical features of superficial bladder cancer.
MATERIALS AND METHODS: This study included 201 healthy controls with a mean ± SD age of 62.35 ± 7.96 years and 123 patients with a mean age of 64.03 ± 11.00 years diagnosed with histopathologically confirmed superficial bladder cancer. The eNOS4a/b polymorphism genotype (aa, bb or ab) was identified by polymerase chain reaction. Blood glutathione and plasma malondialdehyde levels were measured by spectrophotometry as an indicator of oxidative stress. We estimated total plasma levels of nitric oxide metabolites using a colorimetric assay kit.
RESULTS: There were no significant differences in age or body mass index between patients and controls. Malondialdehyde and nitric oxide metabolite levels were statistically significantly increased (p = 0.000 and 0.024, respectively) and glutathione levels were decreased (p = 0.000) in patients with superficial bladder cancer. The bb genotype of the eNOS4a/b polymorphism is the most frequent one in the Turkish population and the aa genotype was significantly more common in patients with superficial bladder cancer (p = 0.000). Also, the aa plus ab genotype was significantly more common in patients with high grade tumors (p = 0.013) and in those with more progression to muscle invasive disease (p = 0.000). This genotype was also a significant independent risk factor for recurrence after adjusting for smoking status, stage, grade and the presence of carcinoma in situ on logistic regression analyses (OR 3.095, 95% CI 1.21-7.86, p = 0.018).
CONCLUSIONS: The current study suggests that a genotype containing the a allele of the eNOS4a/b polymorphism may be a risk factor for bladder cancer. Additionally, patients harboring the aa plus ab genotype are more likely to experience tumor recurrence and progression.
Ziaei SA, Samzadeh M, Jamaldini SH, et al.Endothelial nitric oxide synthase Glu298Asp polymorphism as a risk factor for prostate cancer.
Int J Biol Markers. 2013 Jan-Mar; 28(1):43-8 [PubMed
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BACKGROUND: The endothelial form of nitric oxide synthases (eNOS) seems to have an important role in vascular development, maintenance of the vascular tone and tumor growth in human prostate cancer (PC). The purpose of this study was to investigate the association between grade and stage of disease, age of diagnosis, vascular or perineural invasion, pre-diagnostic plasma prostate-specific antigen (PSA) levels, prostate cancer risk and Glu298Asp polymorphism of the eNOS gene.
METHODS: Ninety-five prostate cancer patients and 111 benign prostate hyperplasia subjects were included. The Glu298Asp polymorphism of the eNOS gene was determined by polymerase chain reaction and restriction fragment length polymorphism
RESULTS: The odds ratio (OR) between the GT and GG polymorphism was 0.76, indicating that the presence of the GT polymorphism decreased the risk of prostate cancer of more than 20% compared to the GG polymorphism. This difference, however, was not statistically significant. The GT polymorphism had an inverse association with cancer grade compared to the reference group (OR=0.47, p value=0.2).
CONCLUSIONS: These results suggest that prostate cancer development is not associated with the Glu298Asp polymorphism of the endothelial nitric oxide synthase gene in our population. Further studies in larger samples are needed to confirm our results and characterize the molecular mechanisms by which eNOS is involved in the susceptibility to prostate cancer.
Jezierski A, Deb-Rinker P, Sodja C, et al.Involvement of NOS3 in RA-Induced neural differentiation of human NT2/D1 cells.
J Neurosci Res. 2012; 90(12):2362-77 [PubMed
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Nitric oxide (NO) plays a key role in neurogenesis as a regulator of cell proliferation and differentiation. NO is synthesized from the amino acid L-arginine by nitric oxide synthases (NOS1, NOS2, and NOS3), which are encoded by separate genes and display different tissue distributions. We used an in vitro model of RA-induced neural differentiation of NT2 cells to examine which of the three NO-synthesizing enzymes is involved in this process. The results revealed a transient induction of NOS3 (known as the constitutively expressed endothelial nitric oxide synthase; eNOS) during the time course of the RA treatment. The peak of gene expression and the nuclear presence of NOS3 protein coincided with cell cycle exit of NT2-derived neuronal precursors. The subsequent analysis of cytosine methylation and histone H3 acetylation of the human NOS3 5' regulatory sequences indicated that epigenetic modifications, especially upstream of the proximal promoter (-734 to -989, relative to exon 2 TSS at +1), were also taking place. NOS1 was expressed only in the differentiated neurons (NT2-N), whereas NOS2 was not expressed at all in this cellular model. Thus, a burst of NO production, possibly required to inhibit neural cell proliferation, was generated by the transient expression of NOS3. This pattern of gene expression, in turn, required epigenetic remodeling of its regulatory region.
Oh NJ, Ryu KY, Jung CN, et al.Expression of endothelial nitric oxide synthase in the uterus of patients with leiomyoma or adenomyosis.
J Obstet Gynaecol Res. 2013; 39(2):536-42 [PubMed
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AIM: To confirm the difference in the expression of endothelial nitric oxide synthase in the normal endometrium and myometrium of women who have leiomyoma or adenomyosis compared with controls, and its correlation with the pathogenesis of menorrhagia or dysmenorrhea in patients with uterine leiomyoma.
METHODS: Fifty-one hysterectomized patients were divided into three groups: (i) patients with leiomyoma (n=24); (ii) those with adenomyosis (n = 19); and (iii) the control group (n=8). The expression of endothelial nitric oxide synthase was confirmed on immunohistochemistry and analyzed using an evaluation nomogram.
RESULTS: The expression of endothelial nitric oxide synthase was significantly higher in the leiomyoma group and the adenomyosis group as compared with the control group. In the subgroup analysis of leiomyoma depending on symptoms (menorrhagia or dysmenorrhea or both), the expression of endothelial nitric oxide synthase was significantly higher in the symptomatic subgroup than the asymptomatic subgroup (endometrium P=0.0029, myometrium P=0.0276).
CONCLUSIONS: Based on the findings that the expression of endothelial nitric oxide synthase was significantly higher in the uterus with leiomyoma or adenomyosis, it can therefore be inferred that nitric oxide might have a pathological effect on the uterus with the above diseases. In particular, it is also presumed that endothelial nitric oxide synthase is closely associated with menorrhagia and dysmenorrhea.
Kim SJ, Lee Y, Kim NY, et al.Pancreatic adenocarcinoma upregulated factor, a novel endothelial activator, promotes angiogenesis and vascular permeability.
Oncogene. 2013; 32(31):3638-47 [PubMed
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Pancreatic adenocarcinoma upregulated factor (PAUF) was recently reported to be a metastasis factor for pancreatic cancer cells. Here, we demonstrate a novel role for PAUF as a potent endothelial activator, promoting both angiogenesis and vascular permeability. Overexpression of PAUF in a mouse pancreatic cancer model resulted in increased tumor vascularity. Recombinant PAUF (rPAUF) enhanced proliferation, migration and capillary-like tube formation of human endothelial cells (ECs), consistently with increased neovascularization in vivo. rPAUF also increased endothelial permeability through the disruption of vascular endothelial-cadherin-facilitated cell-cell junctions in vitro and induced vascular leakage in mouse skin. These effects were attenuated upon treatment with an antibody against PAUF. Moreover, PAUF evoked a time- and dose-dependent activation of extracellular signal-regulated kinase (ERK)1/2, AKT and endothelial NO synthase (eNOS) in ECs, which are closely linked to rPAUF-induced angiogenesis. Finally, rPAUF upregulated the expression of C-X-C chemokine receptor 4 (CXCR4) in ECs and potentiated the in vitro and in vivo EC angiogenic responses to stromal cell-derived factor-1 (SDF-1), a ligand for CXCR4. Taken together, these data demonstrate that PAUF has a novel function in promoting angiogenesis and vascular permeability. Our findings suggest new possibilities for PAUF's role in the pathogenesis of angiogenesis-dependent diseases.
BACKGROUND: Emodin has been showed to induce apoptosis of pancreatic cancer cells and inhibit tumor growth in our previous studies. This study was designed to investigate whether emodin could inhibit the angiogenesis of pancreatic cancer tissues and its mechanism.
METHODOLOGY/PRINCIPAL FINDING: In accordance with our previous study, emodin inhibited pancreatic cancer cell growth, induced apoptosis, and enhanced the anti-tumor effect of gemcitabine on pancreatic caner cells in vitro and in vivo by inhibiting the activity of NF-κB. Here, for the first time, we demonstrated that emodin inhibited tumor angiogenesis in vitro and in implanted pancreatic cancer tissues, decreased the expression of angiogenesis-associated factors (NF-κB and its regulated factors VEGF, MMP-2, MMP-9, and eNOS), and reduced eNOS phosphorylation, as evidenced by both immunohistochemistry and western blot analysis of implanted tumors. In addition, we found that emodin had no effect on VEGFR expression in vivo.
CONCLUSIONS/SIGNIFICANCE: Our results suggested that emodin has potential anti-tumor effect on pancreatic cancer via its dual role in the promotion of apoptosis and suppression of angiogenesis, probably through regulating the expression of NF-κB and NF-κB-regulated angiogenesis-associated factors.