BARD1 mediates TGF-β signaling in pulmonary fibrosis

Abstract

BackgroundIdiopathic 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.MethodsWe 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.ResultsFL 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0278-3) contains supplementary material, which is available to authorized users.

Baicalin attenuates bleomycin-induced pulmonary fibrosis via adenosine A2a receptor related TGF-β1-induced ERK1/2 signaling pathway

“…Finally the deposition of ECM leads to the development of IPF [ 34 – 36 ]. TGF-β1 is thought to drive the cardinal processes to the initiation and progression of lung fibrosis, including inflammatory response, epithelial cell apoptosis, EMT, fibroblast proliferation, and collagen deposition [ 37 ]. In our model, the immunohistochemistry and western analysis shown the expression of TGF-β1 increased to varying degrees after baicalin administration to both WT and KO mice.…”

Immune Mechanisms in Pulmonary Fibrosis

“…Recently, another study showed that TGF-β1 increases vascular cell adhesion molecule 1 and promotes fibroblast proliferation in IPF patients (147). Furthermore, TGF-β1 enhances fibroblast proliferation and promotes pulmonary fibrosis via BARD1 (BRCA1 Associated RING Domain 1) pathway (148).…”

Potential regulatory role of circular RNA in idiopathic pulmonary fibrosis

“…Yang et al ( 29 ) reported that ZDHHC4, which causes a significant downregulation of circRNAhsa_circ_104310, is a significant methylation marker to regulate the expression of large groups of genes in a trans-acting manner in IPF. André et al ( 30 ) demonstrated that BRCA1-associated RING domain 1, the host gene of hsa_circRNA_102910, regulates lung epithelial cell damage and fibroblast proliferation by acting as a mediator of hypoxia and TGF-β may be a novel target for IPF treatment. hsa_circRNA_102348 is spliced from the elongator acetyltransferase complex subunit 2 gene, which encodes a general binding partner or chaperone for the activation and nuclear translocation of signal transducer and activator of transcription (STAT)3 ( 31 ) and may regulate the JAK/STAT signalling pathway.…”