RT Journal Article
SR Electronic
T1 MiR-214-3p, a new fibromiR involved in the pathogenesis of idiopathic pulmonary fibrosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1731
VO 44
IS Suppl 58
A1 Savary, Grégoire
A1 Buscot, Matthieu
A1 Dewaeles, Edmone
A1 Henaoui, Imène Sarah
A1 Quarré, Stéphanie
A1 Courcot, Elisabeth
A1 Cauffiez, Christelle
A1 Barbry, Pascal
A1 Perrais, Michael
A1 Mari, Bernard
A1 Pottier, Nicolas
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/1731.abstract
AB Recent evidence has unveiled a critical role of miRNAs in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). In particular, we established miR-199a-5p as a major regulator of lung fibroblast/myofibroblasts differentiation by targeting CAV1, a key player in TGFβ signaling (Lino Cardenas, CL et al. Plos Genetics 2013,9:2). Interestingly, miR-199a-5p belongs to the miR-199a/214 gene cluster encoded by the DNM3os (Dynamin 3 Opposite Strand) transcript. TGFβ stimulation of lung fibroblasts enhanced the expression of DNM3os and miR-199a/214, suggesting a transcriptional regulation of the whole cluster. In order to establish the role of this cluster in the pathogenesis of IPF, we focused on the contribution of miR-214 to fibrotic mechanisms.First, we demonstrated that miR-214 overexpression was sufficient to induce lung fibroblast differentiation into myofibroblasts. Next, we addressed the importance of miR-214 in the molecular events underlying TGFβ signaling. Transcriptomic analysis of miR-214 overexpressing lung fibroblasts led us to identify miR-214 targets that are clearly involved in the non-canonical TGFβ pathway. Using similar approaches, we also reported that miR-214 was a potent regulator of the HGF/COX-2/PGE2 axis, which is crucial for lung epithelial repair.Overall, we show here that the miR-199a/214 cluster functions as a key regulator of both canonic and non-canonic TGFβ pathways and as a critical actor of myofibroblast differentiation and epithelial-mesenchymal interactions. Finally, as aberrant lung expression of miR-199a and miR-214 has also been found in IPF patients, the inhibition of this cluster may represent a new effective therapeutic option for this devastating disease.