Elsevier

Nitric Oxide

Volume 84, 1 March 2019, Pages 1-6
Nitric Oxide

Effects of eNOS gene polymorphisms on individual susceptibility to cancer: A meta-analysis

https://doi.org/10.1016/j.niox.2018.12.006Get rights and content

Highlights

  • This is so far the most comprehensive evidence-based meta-analysis on eNOS polymorphisms and cancer.

  • Our findings indicated that rs1799983, rs2070744 and rs869109213 polymorphisms may serve as genetic biomarkers of cancer in certain ethnicities.

Abstract

Background

Whether endothelial nitric oxide synthase (eNOS) polymorphisms are implicated in cancer development remains controversial. Therefore, we performed this study to obtain a more conclusive result on associations between eNOS polymorphisms and cancer.

Methods

Literature retrieve was conducted in PubMed, Medline and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.

Results

Forty-one studies were enrolled for analyses. Pooled overall analyses showed that rs1799983 (dominant model: p = 0.01; recessive model: p = 0.007; allele model: p = 0.005), rs2070744 (recessive model: p = 0.004) and rs869109213 (recessive model: p < 0.0001; allele model: p = 0.02) polymorphisms were all significantly associated with individual susceptibility to cancer. Further subgroup analyses revealed that rs2070744 and rs869109213 polymorphisms were only significantly associated with individual susceptibility to cancer in Caucasians, whereas the rs1799983 polymorphism was significantly associated with individual susceptibility to cancer in both Caucasians and Asians.

Conclusions

Our findings indicated that rs1799983, rs2070744 and rs869109213 polymorphisms may serve as genetic biomarkers of cancer in certain ethnicities.

Introduction

Cancer is a pivotal health problem all over the world [1]. In spite of enormous advances achieved in diagnosis and treatment over the past decades, it still accounts for over 22000 deaths every day [2]. Until now, the exact cause of cancer is still unknown. Although irregular life, smoking, heavy alcohol intake and chronic viral infection were already proved to be potential pathogenic factors of cancer by previous epidemiological investigations [3,4], the fact that a great inter-individual variability in disease susceptibility existed in these exposed to above mentioned carcinogenic factors suggested that genetic factors are also involved in cancer development.

Nitric oxide (NO) is a short-lived small molecule that could exert protection effects against free radicals, but at excessive concentrations, NO or its derivatives might cause DNA damage and lead to cancer development. Therefore, balance of NO level is critical for cancer prevention [5,6]. The endothelial nitric oxide synthase (eNOS), encoded by the eNOS gene located on chromosome 7q35-36, plays a pivotal role in regulating synthesis of NO [7], and previous studies showed that eNOS may also be implicated in cancer development. Firstly, eNOS expression levels were found to be significantly elevated in various cancerous tissues [[8], [9], [10], [11]]. Secondly, it was evident that eNOS was also involved in multiple cancer-related events such as angiogenesis, invasion and metastasis [[12], [13], [14]]. Therefore, it is biologically plausible that eNOS polymorphisms, which may alter the expression level of eNOS and impact synthesize of NO, may serve as genetic biomarkers of cancer. So far, associations between eNOS polymorphisms and individual susceptibility to cancer remain controversial. Therefore, we performed the present meta-analysis to better explore potential roles of eNOS polymorphisms in cancer development.

Section snippets

Literature search and inclusion criteria

This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline [15]. Potentially related literature (published before August 2018) were retrieved from PubMed, Medline and Embase using the following searching strategy: (endothelial nitric oxide synthase OR nitric oxide synthase type III OR eNOS OR NOS3) AND (polymorphism OR variant OR mutation OR genotype OR allele) AND (cancer OR tumor OR carcinoma OR neoplasm OR malignancy). Furthermore,

Characteristics of included studies

We found 428 potential relevant articles. Among these articles, a total of 41 eligible studies were finally included for synthetic analyses (see Fig. 1) [[19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59]]. The NOS score of eligible articles ranged from 7 to 8, which indicated that all included studies

Discussion

To the best of our knowledge, this is so far the most comprehensive meta-analysis on associations between eNOS polymorphisms and cancer, and our pooled analyses demonstrated that rs1799983, rs2070744 and rs869109213 polymorphisms were all significantly associated with individual susceptibility to cancer. Further subgroup analyses revealed that rs2070744 and rs869109213 polymorphisms were only significantly associated with individual susceptibility to cancer in Caucasians, whereas the rs1799983

Conclusions

In conclusion, our meta-analysis suggested that rs1799983, rs2070744 and rs869109213 polymorphisms may serve as genetic biomarkers of cancer in certain ethnicities. However, further well-designed studies are still warranted to confirm our findings.

Authors' contributions

Jun Nan and Dahe Ge conceived of the study, participated in its design. Jun Nan and Yaqing Liu conducted the systematic literature review. Yaqing Liu and Chunjin Xu performed data analyses. Jun Nan and Dahe Ge drafted the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Funding

None.

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study formal consent is not required.

Acknowledgments

None.

References (65)

  • E.K. Riener et al.

    Polymorphisms of the endothelial nitric oxide synthase gene in women with vulvar cancer

    Gynecol. Oncol.

    (2004)
  • C. Ryk et al.

    Polymorphisms in nitric-oxide synthase 3 may influence the risk of urinary-bladder cancer

    Nitric Oxide

    (2011)
  • M.R. Safarinejad et al.

    Effects of the T-786C, G894T, and Intron 4 VNTR (4a/b) polymorphisms of the endothelial nitric oxide synthase gene on the risk of prostate cancer

    Urol. Oncol.

    (2013)
  • C.W. Su et al.

    Associations of genetic variations of the endothelial nitric oxide synthase gene and environmental carcinogens with oral cancer susceptibility and development

    Nitric Oxide

    (2018)
  • R. Siegel et al.

    Cancer statistics, 2014

    Ca - Cancer J. Clin.

    (2014)
  • J. Ferlay et al.

    Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012

    Int. J. Canc.

    (2015)
  • R.F. de Menezes et al.

    Alcohol consumption and risk of cancer: a systematic literature review

    Asian Pac. J. Cancer Prev. APJCP

    (2013)
  • A.J. Burke et al.

    The yin and yang of nitric oxide in cancer progression

    Carcinogenesis

    (2013)
  • S.K. Choudhari et al.

    Nitric oxide and cancer: a review

    World J. Surg. Oncol.

    (2013)
  • C. Heiss et al.

    Central role of eNOS in the maintenance of endothelial homeostasis

    Antioxidants Redox Signal.

    (2015)
  • N.J. Oh et al.

    Expression of endothelial nitric oxide synthase in the uterus of patients with leiomyoma or adenomyosis

    J. Obstet. Gynaecol. Res.

    (2013)
  • N. Yagihashi et al.

    Increased in situ expression of nitric oxide synthase in human colorectal cancer

    Virchows Arch.

    (2000)
  • S. MacLauchlan et al.

    Endothelial nitric oxide synthase controls the expression of the angiogenesis inhibitor thrombospondin 2

    Proc. Natl. Acad. Sci. U. S. A.

    (2011)
  • V. Prabhu et al.

    Nitric oxide: pros and cons in tumor progression

    Immunopharmacol. Immunotoxicol.

    (2010)
  • L.C. Jadeski et al.

    Nitric oxide promotes murine mammary tumour growth and metastasis by stimulating tumour cell migration, invasiveness and angiogenesis

    Int. J. Canc.

    (2000)
  • D. Moher et al.

    PRISMA group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    Ann. Intern. Med.

    (2009)
  • A. Stang

    Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses

    Eur. J. Epidemiol.

    (2010)
  • O. Abdel-Rahman et al.

    Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: an updated systematic review of 81 epidemiological studies

    J. Evid. Base Med.

    (2017)
  • J. Zhang et al.

    Four polymorphisms in the IL-22 gene and the risk of cancer: a meta-analysis

    J. Evid. Base Med.

    (2018)
  • S. Arıkan et al.

    The effects of NOS3 Glu298Asp variant on colorectal cancer risk and progression in Turkish population

    Mol. Biol. Rep.

    (2012)
  • C. Basmaci et al.

    Effects of TNFα, NOS3, MDR1 gene polymorphisms on clinical parameters, prognosis and survival of multiple myeloma cases

    Asian Pac. J. Cancer Prev. APJCP

    (2016)
  • A. Branković et al.

    Endothelial nitric oxide synthase gene polymorphisms and prostate cancer risk in Serbian population

    Int. J. Exp. Pathol.

    (2013)
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