TY - JOUR
T1 - BARD1 mediates TGF-β signaling in pulmonary fibrosis
AU - André, Pierre Alain
AU - Prele, Cecilia
AU - Vierkotten, Sarah
AU - Carnesecchi, Stéphanie
AU - Donati, Yves
AU - Chambers, Rachel C.
AU - Pache, Jean Claude
AU - Crestani, Bruno
AU - Barazzone-Argiroffo, Constance
AU - Königshoff, Melanie
AU - Laurent, Geoff
AU - Irminger-Finger, Irmgard
PY - 2015/9/29
Y1 - 2015/9/29
N2 - Background: Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-β signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1β, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis. Methods: We investigated BARD1 expression as a function of TGF-β in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients. Results: FL BARD1 and BARD1β were upregulated in response to TGF-β in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1β in fibrotic tissues. Conclusion: Our data suggest that FL BARD1 and BARD1β might be mediators of pleiotropic effects of TGF-β. In particular BARD1β might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment.
AB - Background: Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-β signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1β, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis. Methods: We investigated BARD1 expression as a function of TGF-β in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients. Results: FL BARD1 and BARD1β were upregulated in response to TGF-β in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1β in fibrotic tissues. Conclusion: Our data suggest that FL BARD1 and BARD1β might be mediators of pleiotropic effects of TGF-β. In particular BARD1β might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment.
KW - Apoptosis
KW - BARD1
KW - Differential splicing
KW - Epithelial-mesenchymal transition (EMT)
KW - Lung fibrosis
KW - Proliferation
KW - TGF-β
UR - http://www.scopus.com/inward/record.url?scp=84942436558&partnerID=8YFLogxK
U2 - 10.1186/s12931-015-0278-3
DO - 10.1186/s12931-015-0278-3
M3 - Article
AN - SCOPUS:84942436558
SN - 1465-9921
VL - 16
SP - 1
EP - 14
JO - Respiratory Research
JF - Respiratory Research
IS - 1
M1 - 118
ER -