title: Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation.
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.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Yael
authors.initials: Y
authors.lastname: Strulovici-Barel
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Salit
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Staudt
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Joumana
authors.initials: J
authors.lastname: Ahmed
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Tilley
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Jenny
authors.initials: J
authors.lastname: Yee-Levin
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Charleen
authors.initials: C
authors.lastname: Hollmann
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Ben-Gary
authors.initials: BG
authors.lastname: Harvey
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kaner
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America; Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Mezey
authors.affiliation: Hoffman-La Roche, Inc, Nutley, New Jersey, United States of America.
authors.forename: Sriram
authors.initials: S
authors.lastname: Sridhar
authors.affiliation: Hoffman-La Roche, Inc, Nutley, New Jersey, United States of America.
authors.forename: Sreekumar G
authors.initials: SG
authors.lastname: Pillai
authors.affiliation: Hoffman-La Roche, Inc, Nutley, New Jersey, United States of America.
authors.forename: Holly
authors.initials: H
authors.lastname: Hilton
authors.affiliation: Hoffman-La Roche, Inc, Nutley, New Jersey, United States of America.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolff
authors.affiliation: Hoffman-La Roche, Inc, Nutley, New Jersey, United States of America.
authors.forename: Hans
authors.initials: H
authors.lastname: Bitter
authors.affiliation: Hoffman-La Roche, Inc, Nutley, New Jersey, United States of America.
authors.forename: Sudha
authors.initials: S
authors.lastname: Visvanathan
authors.affiliation: Hoffman-La Roche, Inc, Nutley, New Jersey, United States of America.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Fine
authors.affiliation: Hoffman-La Roche, Inc, Nutley, New Jersey, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stevenson
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000328:Adult; D001999:Bronchoscopy; D002454:Cell Differentiation; D016000:Cluster Analysis; D003367:Cotinine / Q000652:urine; D015536:Down-Regulation; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009538:Nicotine / Q000652:urine; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D012907:Smoking; D016540:Smoking Cessation; D015854:Up-Regulation; D060449:Wnt Signaling Pathway
chemical_list: D035683:MicroRNAs; D009538:Nicotine; D003367:Cotinine