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TitleUnique tracheal fluid microRNA signature predicts response to FETO in patients with congenital diaphragmatic hernia
Author(s)Terra, Patrícia Daniela Pereira
Deprest, Jan A.
Kholdebarin, Ramin
Khoshgoo, Naghmeh
DeKoninck, Philip
Munck, Anne A. Boerema-De
Wang, Jinxia
Zhu, Fuqin
Rottier, Robbert J.
Iwasiow, Barbara M.
Pinto, Jorge Correia
Tibboel, Dick
Post, Martin
Keijzer, Richard
KeywordsCongenital diaphragmatic hernia
Pulmonary hypoplasia
TGF-β signaling
Tracheal occlusion
Issue date2015
JournalAnnals of surgery
Abstract(s)OBJECTIVE AND BACKGROUND: Our objective was to determine the fetal in vivo microRNA signature in hypoplastic lungs of human fetuses with severe isolated congenital diaphragmatic hernia (CDH) and changes in tracheal and amniotic fluid of fetuses undergoing fetoscopic endoluminal tracheal occlusion (FETO) to reverse severe lung hypoplasia due to CDH. METHODS:: We profiled microRNA expression in prenatal human lungs by microarray analysis. We then validated this signature with real-time quantitative polymerase chain reaction in tracheal and amniotic fluid of CDH patients undergoing FETO. We further explored the role of miR-200b using semiquantitative in situ hybridization and immunohistochemistry for TGF-ß2 in postnatal lung sections. We investigated miR-200b effects on TGF-ß signaling using a SMAD-luciferase reporter assay and Western blotting for phospho-SMAD2/3 and ZEB-2 in cultures of human bronchial epithelial cells. RESULTS:: CDH lungs display an increased expression of 2 microRNAs: miR-200b and miR-10a as compared to control lungs. Fetuses undergoing FETO display increased miR-200 expression in their tracheal fluid at the time of balloon removal. Future survivors of FETO display significantly higher miR-200 expression than those with a limited response. miR-200b was expressed in bronchial epithelial cells and vascular endothelial cells. TGF-ß2 expression was lower in CDH lungs. miR-200b inhibited TGF-ß-induced SMAD signaling in cultures of human bronchial epithelial cells. CONCLUSIONS:: Human fetal hypoplastic CDH lungs have a specific miR-200/miR-10a signature. Survival after FETO is associated with increased miR-200 family expression. miR-200b overexpression in CDH lungs results in decreased TGF-ß/SMAD signaling.
Description"Epub ahead of print 2015 Jan 5"
Publisher version
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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