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      Effect of a single nucleotide polymorphism in miR-146a on COX-2 protein expression and lung function in smokers with chronic obstructive pulmonary disease

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          Abstract

          Objective

          To evaluate the effect of a single nucleotide polymorphism (rs2910164) in the miR-146a precursor on the expression level of miR-146a, cyclooxygenase-2 (COX2), and production of prostaglandin E2 (PGE2) in lung tissue harvested from smokers with chronic obstructive pulmonary disease, as well as the lung function and disease stages from the same patient population.

          Methods and results

          One-hundred and sixty-eight smokers with diagnosed chronic obstructive pulmonary disease were recruited. The patients were genotyped for rs2910164 polymorphism using Sanger sequencing, and their lung function/disease stages were evaluated following Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Meanwhile, messenger ribonucleic acid and protein expression levels of miR-146a and COX2 as well as PGE2 production were determined in 66 lung tissue samples collected in the patients who received surgical treatment. We confirmed that COX2 is a validated target of miR-146a in human fibroblast cells, and identified the differential expression patterns of miR-146a and COX2 in each rs2910164 genotype group. We observed a significant association between rs2910164 in miR-146a and the levels of either COX2 or PGE2 using real-time polymerase chain reaction and Western blot. Consistently, we were able to demonstrate that the rs2910164 single nucleotide polymorphism has a functional effect on the baseline lung function in the study population.

          Conclusion

          In the present study, the rs2910164 CC and GC genotype was found to be associated with an improved lung function and milder disease stages, at least partially, mediated by its ability to increase in COX2 expression and PGE2 production.

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          Most cited references 42

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          Genetic variation in microRNA networks: the implications for cancer research.

          Many studies have highlighted the role that microRNAs have in physiological processes and how their deregulation can lead to cancer. More recently, it has been proposed that the presence of single nucleotide polymorphisms in microRNA genes, their processing machinery and target binding sites affects cancer risk, treatment efficacy and patient prognosis. In reviewing this new field of cancer biology, we describe the methodological approaches of these studies and make recommendations for which strategies will be most informative in the future.
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            MicroRNAs: novel biomarkers for human cancer.

            MicroRNAs (miRNAs), small RNA molecules of approximately 22 nucleotides, have been shown to be up- or downregulated in specific cell types and disease states. These molecules have become recognized as one of the major regulatory gatekeepers of coding genes in the human genome. We review the structure, nomenclature, mechanism of action, technologies used for miRNA detection, and associations of miRNAs with human cancer. miRNAs are produced in a tissue-specific manner, and changes in miRNA within a tissue type can be correlated with disease status. miRNAs appear to regulate mRNA translation and degradation via mechanisms that are dependent on the degree of complementarity between the miRNA and mRNA molecules. miRNAs can be detected via several methods, such as microarrays, bead-based arrays, and quantitative real-time PCR. The tissue concentrations of specific miRNAs have been associated with tumor invasiveness, metastatic potential, and other clinical characteristics for several types of cancers, including chronic lymphocytic leukemia, and breast, colorectal, hepatic, lung, pancreatic, and prostate cancers. By targeting and controlling the expression of mRNA, miRNAs can control highly complex signal-transduction pathways and other biological pathways. The biologic roles of miRNAs in cancer suggest a correlation with prognosis and therapeutic outcome. Further investigation of these roles may lead to new approaches for the categorization, diagnosis, and treatment of human cancers.
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              Genetic variants of miRNA sequences and non-small cell lung cancer survival.

              Recent evidence indicates that small noncoding RNA molecules known as microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Mutation, misexpression, and altered mature miRNA processing are implicated in carcinogenesis and tumor progression. Because SNPs in pre-miRNAs could alter miRNA processing, expression, and/or binding to target mRNA, we conducted a systematic survey of common pre-miRNA SNPs and their surrounding regions and evaluated in detail the association of 4 of these SNPs with the survival of individuals with non-small cell lung cancer (NSCLC). When we assumed that disease susceptibility was inherited as a recessive phenotype, we found that the rs11614913 SNP in hsa-mir-196a2 was associated with survival in individuals with NSCLC. Specifically, survival was significantly decreased in individuals who were homozygous CC at SNP rs11614913. In the genotype-phenotype correlation analysis of 23 human lung cancer tissue samples, rs11614913 CC was associated with a statistically significant increase in mature hsa-mir-196a expression but not with changes in levels of the precursor, suggesting enhanced processing of the pre-miRNA to its mature form. Furthermore, binding assays revealed that the rs11614913 SNP can affect binding of mature hsa-mir-196a2-3p to its target mRNA. Therefore, the rs11614913 SNP in hsa-mir-196a2 may be a prognostic biomarker for NSCLC. Further characterization of miRNA SNPs may open new avenues for the study of cancer and therapeutic interventions.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2015
                04 March 2015
                : 10
                : 463-473
                Affiliations
                [1 ]Department of Respiratory Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China
                [2 ]Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China
                [3 ]Hefei Prevention and Treatment Center for Occupational Diseases, Hefei, People’s Republic of China
                [4 ]Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
                [5 ]Division of Pulmonary/Critical Care Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA
                Author notes
                Correspondence: Geng-yun Sun, Department of Respiratory Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China, Tel +86 551 6292 2904, Fax +86 551 6292 2904, Email gengyun_sun@ 123456163.com

                *These authors contributed equally to this work

                Article
                copd-10-463
                10.2147/COPD.S74345
                4354402
                © 2015 Wang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Respiratory medicine

                lung function, snp, copd, cox-2, mir-146a

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