MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease
| Autor: | Eric Finnemore, C. Magnus Sköld, Maurizio Chioccioli, Xiting Yan, Maor Sauler, Isabel S. Bazan, Jose L. Gomez, Åsa M. Wheelock, Clemente J. Britto, Joann B. Sweasy, Feng Wan, Chuanxing Li, Willy Roque, Veronique Neumeister, Qile Dai, Ranjit S. Bindra, Patty J. Lee, Jessica Nouws, Naftali Kaminski, So-Jin Kim |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine DNA Repair Pulmonology DNA repair DNA damage Apoptosis Cell Line Cigarette Smoking Cohort Studies Pathogenesis Mice Mice Inbred AKR Pulmonary Disease Chronic Obstructive 03 medical and health sciences 0302 clinical medicine DNA Repair Protein microRNA medicine Animals Humans COPD RNA Messenger Lung Aged Bcl-2-Like Protein 11 BRCA1 Protein business.industry General Medicine Middle Aged medicine.disease respiratory tract diseases Disease Models Animal MicroRNAs 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Medicine Female Disease Susceptibility Transcriptome business DNA Damage Research Article |
| Zdroj: | JCI Insight JCI Insight, Vol 6, Iss 2 (2021) |
| ISSN: | 2379-3708 |
| Popis: | The pathogenesis of chronic obstructive pulmonary disease (COPD) involves aberrant responses to cellular stress caused by chronic cigarette smoke (CS) exposure. However, not all smokers develop COPD and the critical mechanisms that regulate cellular stress responses to increase COPD susceptibility are not understood. Because microRNAs are well-known regulators of cellular stress responses, we evaluated microRNA expression arrays performed on distal parenchymal lung tissue samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA that best correlated with radiographic emphysema and validated this finding in multiple cohorts. In a CS exposure mouse model, inhibition of miR-24-3p increased susceptibility to apoptosis, including alveolar type II epithelial cell apoptosis, and emphysema severity. In lung epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue, and BIM and BRCA1 expression inversely correlated with miR-24-3p. We concluded that miR-24-3p, a regulator of the cellular response to DNA damage, is decreased in COPD, and decreased miR-24-3p increases susceptibility to emphysema through increased BIM and apoptosis. miR-24-3p, a regulator of the DNA damage response, is reduced in chronic obstructive pulmonary disease lung tissue and inhibits susceptibility to epithelial apoptosis and emphysema. |
| Databáze: | OpenAIRE |
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