MiR-101 and miR-144 regulate the expression of the CFTR chloride channel in the lung

• Published in: PloS one Vol. 7; no. 11; p. e50837
• Main Authors: Hassan, Fatemat, Nuovo, Gerard J, Crawford, Melissa, Boyaka, Prosper N, Kirkby, Stephen, Nana-Sinkam, Serge P, Cormet-Boyaka, Estelle
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.11.2012; Public Library of Science (PLoS)
• Subjects: 3' Untranslated regions; 3' Untranslated Regions - genetics; Air Pollutants - toxicity; Air pollution; Animals; Base Sequence; Biology; Biomarkers; Bronchi - pathology; Cadmium; Cadmium - toxicity; Cancer; Cell Line; Chemistry; Chloride; Chlorides; Chronic infection; Chronic obstructive lung disease; Chronic obstructive pulmonary disease; Cigarette smoke; Cigarette smoking; Cigarettes; Critical care; Cystic fibrosis; Cystic fibrosis transmembrane conductance regulator; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Disease control; Diseases; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Gene expression; Gene Expression Regulation - drug effects; Genes; Health aspects; Homeostasis; Humans; In vivo methods and tests; Internal medicine; Kinases; Laboratory animals; Leukemia; Lung - metabolism; Lung - pathology; Lung diseases; Lungs; Medicine; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular Sequence Data; Obstructive lung disease; Patients; Penicillin; Phosphatase; Pollutants; Proteins; Pulmonary Disease, Chronic Obstructive - genetics; Pulmonary Disease, Chronic Obstructive - pathology; Respiratory tract; Smoke; Smoking; Smoking - adverse effects; Smoking - genetics; Up-Regulation - drug effects; Up-Regulation - genetics; United States > US; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0050837

The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride channel that plays a critical role in the lung by maintaining fluid homeostasis. Absence or malfunction of CFTR leads to Cystic Fibrosis, a disease characterized by chronic infection and inflammation. We recently reported that air pollutants such as cigarette smoke and cadmium negatively regulate the expression of CFTR by affecting several steps in the biogenesis of CFTR protein. MicroRNAs (miRNAs) have recently received a great deal of attention as both biomarkers and therapeutics due to their ability to regulate multiple genes. Here, we show that cigarette smoke and cadmium up-regulate the expression of two miRNAs (miR-101 and miR-144) that are predicted to target CFTR in human bronchial epithelial cells. When premature miR-101 and miR-144 were transfected in human airway epithelial cells, they directly targeted the CFTR 3'UTR and suppressed the expression of the CFTR protein. Since miR-101 was highly up-regulated by cigarette smoke in vitro, we investigated whether such increase also occurred in vivo. Mice exposed to cigarette smoke for 4 weeks demonstrated an up-regulation of miR-101 and suppression of CFTR protein in their lungs. Finally, we show that miR-101 is highly expressed in lung samples from patients with severe chronic obstructive pulmonary disease (COPD) when compared to control patients. Taken together, these results suggest that chronic cigarette smoking up-regulates miR-101 and that this miRNA could contribute to suppression of CFTR in the lungs of COPD patients.