MicroRNA-9 downregulates the ANO1 chloride channel and contributes to cystic fibrosis lung pathology

• Published in: Nature communications 2017-09, Vol.8 (1), p.710-11, Article 710
• Main Authors: Sonneville, Florence, Ruffin, Manon, Coraux, Christelle, Rousselet, Nathalie, Le Rouzic, Philippe, Blouquit-Laye, Sabine, Corvol, Harriet, Tabary, Olivier
• Format: Article
• Language: English
• Subjects: 3' Untranslated regions; 631/154/555; 631/337/384/331; Animal models; Calcium channels; Calcium transport; Cystic fibrosis; Epithelial cells; Human health and pathology; Humanities and Social Sciences; Ion transport; Life Sciences; Lungs; MicroRNAs; miRNA; Mucus; multidisciplinary; Pathology; Respiratory tract; Ribonucleic acid; RNA; Rodents; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00813-z

Cystic fibrosis results from reduced cystic fibrosis transmembrane conductance regulator protein activity leading to defective epithelial ion transport. Ca 2+ -activated Cl − channels mediate physiological functions independently of cystic fibrosis transmembrane conductance regulator. Anoctamin 1 (ANO1/TMEM16A) was identified as the major Ca 2+ -activated Cl − channel in airway epithelial cells, and we recently demonstrated that downregulation of the anoctamin 1 channel in cystic fibrosis patients contributes to disease severity via an unknown mechanism. Here we show that microRNA-9 (miR-9) contributes to cystic fibrosis and downregulates anoctamin 1 by directly targeting its 3′UTR. We present a potential therapy based on blockage of miR-9 binding to the 3′UTR by using a microRNA target site blocker to increase anoctamin 1 activity and thus compensate for the cystic fibrosis transmembrane conductance regulator deficiency. The target site blocker is tested in in vitro and in mouse models of cystic fibrosis, and could be considered as an alternative strategy to treat cystic fibrosis. Downregulation of the anoctamin 1 calcium channel in airway epithelial cells contributes to pathology in cystic fibrosis. Here the authors show that microRNA-9 targets anoctamin 1 and that inhibiting this interaction improves mucus dynamics in mouse models.