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

Griet Conickx UGent, Pieter Mestdagh UGent, Francisco Avila Cobos UGent, Fien Verhamme UGent, Tania Maes UGent, Bart M Vanaudenaerde, Leen Seys UGent, Lies Lahousse UGent, Richard Y Kim, Alan C Hsu, et al. (2017) AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. 195(1). p.43-56
abstract
RATIONALE: Since aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis, we aimed to identify dysregulated miRNAs in lung tissue of patients with COPD. METHODS: We performed miRNA and mRNA profiling - using high throughput stem-loop RT-qPCR 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 microRNA-218-5p (miR-218-5p) was validated by RT-qPCR in an independent cohort of 71 patients, an in vivo murine model of COPD, and primary human bronchial epithelial cells (HBECs). 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 both smokers without airflow limitation and in patients with COPD, compared to never smokers. Decreased pulmonary expression of miR-218-5p was validated in an independent validation cohort, in cigarette smoke-exposed mice and in HBECs. 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 url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
COPD, miR-218, lung, microRNA, chronic obstructive pulmonary disease, microRNA-218, CIGARETTE-SMOKE, GENE-EXPRESSION, COPD, LUNG, MICE, IDENTIFICATION, INFLAMMATION, GENOMICS, PATHWAY, SPUTUM
journal title
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Am. J. Respir. Crit. Care Med.
volume
195
issue
1
pages
43 - 56
Web of Science type
Article
Web of Science id
000390982100014
ISSN
1073-449X
DOI
10.1164/rccm.201506-1182OC
language
English
UGent publication?
yes
classification
A1
additional info
the last two authors contributed equally to the supervision of the manuscript
copyright statement
I have transferred the copyright for this publication to the publisher
id
8137206
handle
http://hdl.handle.net/1854/LU-8137206
date created
2016-11-10 09:00:51
date last changed
2017-05-31 12:30:44
@article{8137206,
  abstract     = {RATIONALE: Since aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis, we aimed to identify dysregulated miRNAs in lung tissue of patients with COPD.
METHODS: We performed miRNA and mRNA profiling - using high throughput stem-loop RT-qPCR 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 microRNA-218-5p (miR-218-5p) was validated by RT-qPCR in an independent cohort of 71 patients, an in vivo murine model of COPD, and primary human bronchial epithelial cells (HBECs). 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 both smokers without airflow limitation and in patients with COPD, compared to never smokers. Decreased pulmonary expression of miR-218-5p was validated in an independent validation cohort, in cigarette smoke-exposed mice and in HBECs. 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.},
  author       = {Conickx, Griet and Mestdagh, Pieter and Avila Cobos, Francisco and Verhamme, Fien and Maes, Tania and Vanaudenaerde, Bart M and Seys, Leen and Lahousse, Lies and Kim, Richard Y and Hsu, Alan C and Wark, Peter A and Hansbro, Philip M and Joos, Guy and Vandesompele, Jo and Bracke, Ken and Brusselle, Guy},
  issn         = {1073-449X},
  journal      = {AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE},
  keyword      = {COPD,miR-218,lung,microRNA,chronic obstructive pulmonary disease,microRNA-218,CIGARETTE-SMOKE,GENE-EXPRESSION,COPD,LUNG,MICE,IDENTIFICATION,INFLAMMATION,GENOMICS,PATHWAY,SPUTUM},
  language     = {eng},
  number       = {1},
  pages        = {43--56},
  title        = {MicroRNA profiling reveals a role for microRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease},
  url          = {http://dx.doi.org/10.1164/rccm.201506-1182OC},
  volume       = {195},
  year         = {2017},
}

Chicago
Conickx, Griet, Pieter Mestdagh, Francisco Avila Cobos, Fien Verhamme, Tania Maes, Bart M Vanaudenaerde, Leen Seys, et al. 2017. “MicroRNA Profiling Reveals a Role for microRNA-218-5p in the Pathogenesis of Chronic Obstructive Pulmonary Disease.” American Journal of Respiratory and Critical Care Medicine 195 (1): 43–56.
APA
Conickx, G., Mestdagh, P., Avila Cobos, F., Verhamme, F., Maes, T., Vanaudenaerde, B. M., Seys, L., et al. (2017). MicroRNA profiling reveals a role for microRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 195(1), 43–56.
Vancouver
1.
Conickx G, Mestdagh P, Avila Cobos F, Verhamme F, Maes T, Vanaudenaerde BM, et al. MicroRNA profiling reveals a role for microRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. 2017;195(1):43–56.
MLA
Conickx, Griet, Pieter Mestdagh, Francisco Avila Cobos, et al. “MicroRNA Profiling Reveals a Role for microRNA-218-5p in the Pathogenesis of Chronic Obstructive Pulmonary Disease.” AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 195.1 (2017): 43–56. Print.