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MiR-214-3p, a new fibromiR involved in the pathogenesis of idiopathic pulmonary fibrosis

Grégoire Savary, Matthieu Buscot, Edmone Dewaeles, Imène Sarah Henaoui, Stéphanie Quarré, Elisabeth Courcot, Christelle Cauffiez, Pascal Barbry, Michael Perrais, Bernard Mari, Nicolas Pottier
European Respiratory Journal 2014 44: 1731; DOI:
Grégoire Savary
1EA4483, Faculté de Médecine de Lille, Pole recherche, Lille, France
2Institut de Pharmacologie Moléculaire et Cellulaire, UMR-6097, Centre National de Recherche Scientifique, Valbonne, France
3Faculté des Sciences, Université de Nice Sophia-Antipolis, Nice, France
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Matthieu Buscot
2Institut de Pharmacologie Moléculaire et Cellulaire, UMR-6097, Centre National de Recherche Scientifique, Valbonne, France
3Faculté des Sciences, Université de Nice Sophia-Antipolis, Nice, France
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Edmone Dewaeles
1EA4483, Faculté de Médecine de Lille, Pole recherche, Lille, France
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Imène Sarah Henaoui
2Institut de Pharmacologie Moléculaire et Cellulaire, UMR-6097, Centre National de Recherche Scientifique, Valbonne, France
3Faculté des Sciences, Université de Nice Sophia-Antipolis, Nice, France
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Stéphanie Quarré
1EA4483, Faculté de Médecine de Lille, Pole recherche, Lille, France
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Elisabeth Courcot
1EA4483, Faculté de Médecine de Lille, Pole recherche, Lille, France
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Christelle Cauffiez
1EA4483, Faculté de Médecine de Lille, Pole recherche, Lille, France
5Faculté de Médecine, Université Lille 2, Lille, France
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Pascal Barbry
2Institut de Pharmacologie Moléculaire et Cellulaire, UMR-6097, Centre National de Recherche Scientifique, Valbonne, France
3Faculté des Sciences, Université de Nice Sophia-Antipolis, Nice, France
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Michael Perrais
4Jaen-Pierre Aubert Recherche Center, U837, Institut National de la Santé et de la Recherche Médicale, Lille, France
5Faculté de Médecine, Université Lille 2, Lille, France
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Bernard Mari
2Institut de Pharmacologie Moléculaire et Cellulaire, UMR-6097, Centre National de Recherche Scientifique, Valbonne, France
3Faculté des Sciences, Université de Nice Sophia-Antipolis, Nice, France
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Nicolas Pottier
1EA4483, Faculté de Médecine de Lille, Pole recherche, Lille, France
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Abstract

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.

  • Idiopathic pulmonary fibrosis
  • Functional genomics
  • Interstitial lung disease (connective tissue disease)
  • © 2014 ERS
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MiR-214-3p, a new fibromiR involved in the pathogenesis of idiopathic pulmonary fibrosis
Grégoire Savary, Matthieu Buscot, Edmone Dewaeles, Imène Sarah Henaoui, Stéphanie Quarré, Elisabeth Courcot, Christelle Cauffiez, Pascal Barbry, Michael Perrais, Bernard Mari, Nicolas Pottier
European Respiratory Journal Sep 2014, 44 (Suppl 58) 1731;

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MiR-214-3p, a new fibromiR involved in the pathogenesis of idiopathic pulmonary fibrosis
Grégoire Savary, Matthieu Buscot, Edmone Dewaeles, Imène Sarah Henaoui, Stéphanie Quarré, Elisabeth Courcot, Christelle Cauffiez, Pascal Barbry, Michael Perrais, Bernard Mari, Nicolas Pottier
European Respiratory Journal Sep 2014, 44 (Suppl 58) 1731;
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