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Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation.

Wang G, Wang R, Strulovici-Barel Y, Salit J, Staudt MR, Ahmed J, Tilley AE, Yee-Levin J, Hollmann C, Harvey BG, Kaner RJ, Mezey JG, Sridhar S, Pillai SG, Hilton H, Wolff G, Bitter H, Visvanathan S, Fine JS, Stevenson CS, Crystal RG - PLoS ONE (2015)

Bottom Line: There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy nonsmokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer.After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway being the top identified enriched pathway of the target genes of the persistent dysregulated miRNAs.In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammatory diseases or lung cancer, it is likely that persistent smoking-related changes in SAE miRNAs play a role in the subsequent development of these disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.

ABSTRACT
Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD) and lung cancer remains significantly higher compared to healthy nonsmokers. Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE), we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 9 healthy nonsmokers and 10 healthy smokers, before and after they quit smoking for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy nonsmokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway being the top identified enriched pathway of the target genes of the persistent dysregulated miRNAs. In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammatory diseases or lung cancer, it is likely that persistent smoking-related changes in SAE miRNAs play a role in the subsequent development of these disorders.

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Volcano plot and unsupervised hierarchical clustering of differentially expressed miRNAs in the small airway epithelium (SAE) of healthy smokers and healthy nonsmokers.A. Volcano plot comparing the expression of 1100 human mature miRNAs in the SAE of smokers vs nonsmokers. There were 25 miRNAs (red) upregulated and 9 miRNAs (blue) downregulated in the SAE of healthy smokers compared to healthy nonsmokers (fold-change >1.5, p<0.01, total 34 miRNAs). X-axis, fold-change; Y-axis, p values. B. Unsupervised hierarchical clustering of 34 differentially expressed miRNAs between healthy smokers (tan rectangle) and healthy nonsmokers (green rectangle). The color bar indicates the relative miRNA expression level.
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pone.0120824.g001: Volcano plot and unsupervised hierarchical clustering of differentially expressed miRNAs in the small airway epithelium (SAE) of healthy smokers and healthy nonsmokers.A. Volcano plot comparing the expression of 1100 human mature miRNAs in the SAE of smokers vs nonsmokers. There were 25 miRNAs (red) upregulated and 9 miRNAs (blue) downregulated in the SAE of healthy smokers compared to healthy nonsmokers (fold-change >1.5, p<0.01, total 34 miRNAs). X-axis, fold-change; Y-axis, p values. B. Unsupervised hierarchical clustering of 34 differentially expressed miRNAs between healthy smokers (tan rectangle) and healthy nonsmokers (green rectangle). The color bar indicates the relative miRNA expression level.

Mentions: Using the criteria of p<0.01, fold-change>1.5, 34 out of 1100 human mature miRNAs were identified as significantly changed in the SAE by smoking (Fig 1A and Table 2). Unsupervised hierarchical clustering of the healthy smokers and healthy nonsmokers based on the 34 significantly expressed miRNAs separated healthy smokers and healthy nonsmokers into two distinct groups (Fig 1B). The majority of the smoking-dependent miRNAs were upregulated in healthy smokers compared to healthy nonsmokers (25 of 34 miRNAs, 74%; Fig 1A and Table 2). The miRNA that was most up-regulated in healthy smokers was miR-143 (p<10–2, 9.1-fold). The miRNA that was most down-regulated in healthy smokers was miR-1246 (p<10–3, -3.8-fold). Two miRNA families were over-expressed in healthy smokers compared to healthy nonsmokers, including the miR-181 family (miR-181a, miR-181b and miRNA-181c) [23] and the miR-133 family (miR-133a, miR-133b) [24]. Three microRNA clusters, miR-199a/miR-214 [25], miR-143/miR-145 [26] and miR-181a/miR-181b, were upregulated by smoking.


Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation.

Wang G, Wang R, Strulovici-Barel Y, Salit J, Staudt MR, Ahmed J, Tilley AE, Yee-Levin J, Hollmann C, Harvey BG, Kaner RJ, Mezey JG, Sridhar S, Pillai SG, Hilton H, Wolff G, Bitter H, Visvanathan S, Fine JS, Stevenson CS, Crystal RG - PLoS ONE (2015)

Volcano plot and unsupervised hierarchical clustering of differentially expressed miRNAs in the small airway epithelium (SAE) of healthy smokers and healthy nonsmokers.A. Volcano plot comparing the expression of 1100 human mature miRNAs in the SAE of smokers vs nonsmokers. There were 25 miRNAs (red) upregulated and 9 miRNAs (blue) downregulated in the SAE of healthy smokers compared to healthy nonsmokers (fold-change >1.5, p<0.01, total 34 miRNAs). X-axis, fold-change; Y-axis, p values. B. Unsupervised hierarchical clustering of 34 differentially expressed miRNAs between healthy smokers (tan rectangle) and healthy nonsmokers (green rectangle). The color bar indicates the relative miRNA expression level.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4401720&req=5

pone.0120824.g001: Volcano plot and unsupervised hierarchical clustering of differentially expressed miRNAs in the small airway epithelium (SAE) of healthy smokers and healthy nonsmokers.A. Volcano plot comparing the expression of 1100 human mature miRNAs in the SAE of smokers vs nonsmokers. There were 25 miRNAs (red) upregulated and 9 miRNAs (blue) downregulated in the SAE of healthy smokers compared to healthy nonsmokers (fold-change >1.5, p<0.01, total 34 miRNAs). X-axis, fold-change; Y-axis, p values. B. Unsupervised hierarchical clustering of 34 differentially expressed miRNAs between healthy smokers (tan rectangle) and healthy nonsmokers (green rectangle). The color bar indicates the relative miRNA expression level.
Mentions: Using the criteria of p<0.01, fold-change>1.5, 34 out of 1100 human mature miRNAs were identified as significantly changed in the SAE by smoking (Fig 1A and Table 2). Unsupervised hierarchical clustering of the healthy smokers and healthy nonsmokers based on the 34 significantly expressed miRNAs separated healthy smokers and healthy nonsmokers into two distinct groups (Fig 1B). The majority of the smoking-dependent miRNAs were upregulated in healthy smokers compared to healthy nonsmokers (25 of 34 miRNAs, 74%; Fig 1A and Table 2). The miRNA that was most up-regulated in healthy smokers was miR-143 (p<10–2, 9.1-fold). The miRNA that was most down-regulated in healthy smokers was miR-1246 (p<10–3, -3.8-fold). Two miRNA families were over-expressed in healthy smokers compared to healthy nonsmokers, including the miR-181 family (miR-181a, miR-181b and miRNA-181c) [23] and the miR-133 family (miR-133a, miR-133b) [24]. Three microRNA clusters, miR-199a/miR-214 [25], miR-143/miR-145 [26] and miR-181a/miR-181b, were upregulated by smoking.

Bottom Line: There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy nonsmokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer.After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway being the top identified enriched pathway of the target genes of the persistent dysregulated miRNAs.In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammatory diseases or lung cancer, it is likely that persistent smoking-related changes in SAE miRNAs play a role in the subsequent development of these disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.

ABSTRACT
Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD) and lung cancer remains significantly higher compared to healthy nonsmokers. Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE), we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 9 healthy nonsmokers and 10 healthy smokers, before and after they quit smoking for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy nonsmokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway being the top identified enriched pathway of the target genes of the persistent dysregulated miRNAs. In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammatory diseases or lung cancer, it is likely that persistent smoking-related changes in SAE miRNAs play a role in the subsequent development of these disorders.

Show MeSH
Related in: MedlinePlus