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.
Highlights
Cigarette smoking, with its >4000 compounds and 1014 oxidants per puff, is the major cause of two major lung disorders, chronic obstructive pulmonary disease (COPD) and bronchogenic carcinoma [1,2,3]
We identified 34 smoking-responsive miRNAs in the small airway epithelium (SAE), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer
This is consistent with the knowledge that while smoking cessation improves respiratory symptoms and bronchial hyper-responsiveness, delays the decline in FEV1 compared to continuing smokers, and reduces the risk for lung cancer [7,39,40], the risk for COPD and lung cancer remains significantly higher compared to healthy nonsmokers despite smoking cessation [7,8]
Summary
With its >4000 compounds and 1014 oxidants per puff, is the major cause of two major lung disorders, chronic obstructive pulmonary disease (COPD) and bronchogenic carcinoma [1,2,3]. Smoking affects the expression of many genes in the airway epithelium, suggesting that the biologic processes involved, likely have a broad influence in gene expression One such class of biologic processes are microRNAs (miRNA), small non-coding endogenous, single-stranded, 17 to 25 nucleotide-long RNAs that are generated by sequential processing from longer transcripts that contain a stem-loop [15]. These small regulatory RNAs modulate gene expression by binding to the 3’ end of target mRNAs, resulting in gene silencing through induction of mRNA cleavage or translational suppression [15,16]. MiRNA profiling studies have shown that miRNAs play a role in lung organogenesis [17,18,19] and that smoking can lead to the dysregulation of miRNAs in the large airway epithelium [20]
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