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