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

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.