MicroRNA profiling reveals a role for MicroRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease

Conickx, G; Mestdagh, P; Cobos, FA; Verhamme, FM; Maes, T; Vanaudenaerde, BM; Seys, LJM; Lahousse, L; Kim, RY; Hsu, AC; Wark, PA; Hansbro, PM; Joos, GF; Vandesompele, J; Bracke, KR; Brusselle, GG

MicroRNA profiling reveals a role for MicroRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease

Conickx, G Mestdagh, P Cobos, FA Verhamme, FM Maes, T Vanaudenaerde, BM Seys, LJM Lahousse, L Kim, RY

Hsu, AC Wark, PA Hansbro, PM

Joos, GF Vandesompele, J Bracke, KR Brusselle, GG

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Publication Type:: Journal Article
Citation:: American Journal of Respiratory and Critical Care Medicine, 2017, 195 (1), pp. 43 - 56
Issue Date:: 2017-01-01

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Field	Value	Language
dc.contributor.author	Conickx, G	en_US
dc.contributor.author	Mestdagh, P	en_US
dc.contributor.author	Cobos, FA	en_US
dc.contributor.author	Verhamme, FM	en_US
dc.contributor.author	Maes, T	en_US
dc.contributor.author	Vanaudenaerde, BM	en_US
dc.contributor.author	Seys, LJM	en_US
dc.contributor.author	Lahousse, L	en_US
dc.contributor.author	Kim, RY https://orcid.org/0000-0002-8709-5270	en_US
dc.contributor.author	Hsu, AC	en_US
dc.contributor.author	Wark, PA	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.contributor.author	Joos, GF	en_US
dc.contributor.author	Vandesompele, J	en_US
dc.contributor.author	Bracke, KR	en_US
dc.contributor.author	Brusselle, GG	en_US
dc.date.issued	2017-01-01	en_US
dc.identifier.citation	American Journal of Respiratory and Critical Care Medicine, 2017, 195 (1), pp. 43 - 56	en_US
dc.identifier.issn	1073-449X	en_US
dc.identifier.uri	http://hdl.handle.net/10453/126240
dc.description.abstract	Rationale: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis. Objectives: To identify dysregulated miRNAs in lung tissue of patients with chronic obstructive pulmonary disease (COPD). Methods: We performed miRNA and mRNA profiling using high throughput stem-loop reverse-transcriptase quantitative polymerase chain reaction and mRNA microarray, respectively, on lung tissue of 30 patients (screening cohort) encompassing 8 never-smokers, 10 smokers without airflow limitation, and 12 smokers with COPD. Differential expression of miRNA-218-5p (miR-218-5p) was validated by reverse-transcriptase quantitative polymerase chain reaction in an independent cohort of 71 patients, an in vivo murine model of COPD, and primary human bronchial epithelial cells. Localization of miR-218-5p was assessed by in situ hybridization. In vitro and in vivo perturbation of miR-218-5p combined with RNA sequencing and gene set enrichment analysis was used to elucidate its functional role in COPD pathogenesis. Measurements and Main Results: Several miRNAs were differentially expressed among the different patient groups. Interestingly, miR-218-5p was significantly down-regulated in smokers without airflow limitation and in patients with COPD compared with never-smokers. Decreased pulmonary expression of miR-218-5p was validated in an independent validation cohort, in cigarette smoke-exposed mice, and in human bronchial epithelial cells. Importantly, expression of miR-218-5p strongly correlated with airway obstruction. Furthermore, cellular localization of miR-218-5p in human and murine lung revealed highest expression of miR-218-5p in the bronchial airway epithelium. Perturbation experiments with a miR-218-5p mimic or inhibitor demonstrated a protective role of miR-218-5p in cigarette smoke-induced inflammation and COPD. Conclusions: We highlight a role for miR-218-5p in the pathogenesis of COPD.	en_US
dc.relation.ispartof	American Journal of Respiratory and Critical Care Medicine	en_US
dc.relation.isbasedon	10.1164/rccm.201506-1182OC	en_US
dc.subject.classification	Respiratory System	en_US
dc.subject.mesh	Lung	en_US
dc.subject.mesh	Bronchi	en_US
dc.subject.mesh	Respiratory Mucosa	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive	en_US
dc.subject.mesh	MicroRNAs	en_US
dc.subject.mesh	Oligonucleotide Array Sequence Analysis	en_US
dc.subject.mesh	Case-Control Studies	en_US
dc.subject.mesh	Gene Expression Profiling	en_US
dc.subject.mesh	Reverse Transcriptase Polymerase Chain Reaction	en_US
dc.subject.mesh	Adult	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.title	MicroRNA profiling reveals a role for MicroRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	195	en_US
utslib.for	1101 Medical Biochemistry and Metabolomics	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	195	en_US

Abstract:

Rationale: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis. Objectives: To identify dysregulated miRNAs in lung tissue of patients with chronic obstructive pulmonary disease (COPD). Methods: We performed miRNA and mRNA profiling using high throughput stem-loop reverse-transcriptase quantitative polymerase chain reaction and mRNA microarray, respectively, on lung tissue of 30 patients (screening cohort) encompassing 8 never-smokers, 10 smokers without airflow limitation, and 12 smokers with COPD. Differential expression of miRNA-218-5p (miR-218-5p) was validated by reverse-transcriptase quantitative polymerase chain reaction in an independent cohort of 71 patients, an in vivo murine model of COPD, and primary human bronchial epithelial cells. Localization of miR-218-5p was assessed by in situ hybridization. In vitro and in vivo perturbation of miR-218-5p combined with RNA sequencing and gene set enrichment analysis was used to elucidate its functional role in COPD pathogenesis. Measurements and Main Results: Several miRNAs were differentially expressed among the different patient groups. Interestingly, miR-218-5p was significantly down-regulated in smokers without airflow limitation and in patients with COPD compared with never-smokers. Decreased pulmonary expression of miR-218-5p was validated in an independent validation cohort, in cigarette smoke-exposed mice, and in human bronchial epithelial cells. Importantly, expression of miR-218-5p strongly correlated with airway obstruction. Furthermore, cellular localization of miR-218-5p in human and murine lung revealed highest expression of miR-218-5p in the bronchial airway epithelium. Perturbation experiments with a miR-218-5p mimic or inhibitor demonstrated a protective role of miR-218-5p in cigarette smoke-induced inflammation and COPD. Conclusions: We highlight a role for miR-218-5p in the pathogenesis of COPD.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/126240