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.

The transcriptome of nitrofen-induced pulmonary hypoplasia in the rat model of congenital diaphragmatic hernia

“…For example, the orthologous hsa-miR-200c-3p that was enriched in the rat lung tissues and upregulated upon nitrofen treatment exhibited seed conservation with its host gene. Our findings, with regard to lung development, are consistent with increasing evidence from human studies on the effects of teratogenic and toxic triggers on miRNA profiling, and reconcile with orthologous studies matching the nitrofen-mediated upregulation of rat miR-101a-5p, -3p and human miR-144-5p in vivo in human airway epithelial cells upon cigarette smoke (16). Both of these miRNAs are also known to target genes associated with lung diseases such as the cystic fibrosis transmembrane conductor regulator gene in human (16).…”

Developmental control ofCFTR: from bioinformatics to novel therapeutic approaches

“…The data confirms previous studies implicating miR-145 and miR-101 as important modulators of CFTR expression [5,6,8,9] and build on them by demonstrating how MBBOs based on these miRNAs can affect CFTR gene expression and CFTR protein function. The authors suggest that the MBBOs may be developed as tools for CFTR correction in people with CF.…”

Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury

“…Although multiple studies exist regarding the regulation of ion channels by miRNAs, [30][31][32] our results demonstrate that miR-21/PTEN/AKT pathway involves LXA 4 and LPS regulation of ENaC-γ protein expression. However, there are three aspects that need to be further addressed.…”

“…27 Recent studies revealed that miR-21 was dynamically regulated in LPS-induced ALI. 28,29 Also, studies have showed that miR-16 upregulated ENaC-β, 30 miR-101 and miR-144 targeted cystic fibrosis transmembrane conductance regulator 3′ UTR, 31 miR-96 and miR-330 bound to the 3' UTR of aquaporin 5. 32 Previous studies demonstrated that each specialized pro-resolving mediator regulated a distinct panel of miRNAs.…”