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MicroRNA-145 Antagonism Reverses TGF-β Inhibition of F508del CFTR Correction in Airway Epithelia.

Abstract：

RATIONALE:MicroRNAs (miRNAs) destabilize mRNA transcripts and inhibit protein translation. miR-145 is of particular interest in cystic fibrosis (CF) as it has a direct binding site in the 3'-untranslated region of CFTR (cystic fibrosis transmembrane conductance regulator) and is upregulated by the CF genetic modifier TGF (transforming growth factor)-β. OBJECTIVES:To demonstrate that miR-145 mediates TGF-β inhibition of CFTR synthesis and function in airway epithelia. METHODS:Primary human CF (F508del homozygous) and non-CF airway epithelial cells were grown to terminal differentiation at the air-liquid interface on permeable supports. TGF-β (5 ng/ml), a miR-145 mimic (20 nM), and a miR-145 antagonist (20 nM) were used to manipulate CFTR function. In CF cells, lumacaftor (3 μM) and ivacaftor (10 μM) corrected mutant F508del CFTR. Quantification of CFTR mRNA, protein, and function was done by standard techniques. MEASUREMENTS AND MAIN RESULTS:miR-145 is increased fourfold in CF BAL fluid compared with non-CF (P < 0.01) and increased 10-fold in CF primary airway epithelial cells (P < 0.01). Exogenous TGF-β doubles miR-145 expression (P < 0.05), halves wild-type CFTR mRNA and protein levels (P < 0.01), and nullifies lumacaftor/ivacaftor F508del CFTR correction. miR-145 overexpression similarly decreases wild-type CFTR protein synthesis (P < 0.01) and function (P < 0.05), and eliminates F508del corrector benefit. miR-145 antagonism blocks TGF-β suppression of CFTR and enhances lumacaftor correction of F508del CFTR. CONCLUSIONS:miR-145 mediates TGF-β inhibition of CFTR synthesis and function in airway epithelia. Specific antagonists to miR-145 interrupt TGF-β signaling to restore F508del CFTR modulation. miR-145 antagonism may offer a novel therapeutic opportunity to enhance therapeutic benefit of F508del CFTR correction in CF epithelia.

journal_name

Am J Respir Crit Care Med

journal_title

American journal of respiratory and critical care medicine

authors

Lutful Kabir F,Ambalavanan N,Liu G,Li P,Solomon GM,Lal CV,Mazur M,Halloran B,Szul T,Gerthoffer WT,Rowe SM,Harris WT

doi

10.1164/rccm.201704-0732OC

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

632-643

issue

eissn

1073-449X

issn

1535-4970

journal_volume

197

pub_type

杂志文章

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MicroRNA-145 Antagonism Reverses TGF-β Inhibition of F508del CFTR Correction in Airway Epithelia.