title: MiR-101 and miR-144 regulate the expression of the CFTR chloride channel in the lung.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Fatemat
authors.initials: F
authors.lastname: Hassan
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.forename: Melissa
authors.initials: M
authors.lastname: Crawford
authors.forename: Prosper N
authors.initials: PN
authors.lastname: Boyaka
authors.forename: Stephen
authors.initials: S
authors.lastname: Kirkby
authors.forename: Serge P
authors.initials: SP
authors.lastname: Nana-Sinkam
authors.forename: Estelle
authors.initials: E
authors.lastname: Cormet-Boyaka
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000393:Air Pollutants / Q000633:toxicity; D000818:Animals; D001483:Base Sequence; D001980:Bronchi / Q000473:pathology; D002104:Cadmium / Q000633:toxicity; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000473:pathology; D012907:Smoking / Q000009:adverse effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D000393:Air Pollutants; C534072:MIRN101 microRNA, human; C581233:MIRN101 microRNA, mouse; C554293:MIRN144 microRNA, human; D035683:MicroRNAs; D002104:Cadmium; D019005:Cystic Fibrosis Transmembrane Conductance Regulator