TGF-Beta Induced BARD1/BARD1-Beta Expression Promotes Lung Fibrosis
In a new study entitled “BARD1 mediates TGF-β signaling in pulmonary fibrosis”, researchers investigated whether the tumor suppressor gene BARD1, previously shown to have a role in lung cancer, is associated with pulmonary fibrosis. They found that TGF-beta, an established factor in promoting fibrosis, induces BARD1 protein expression increase, which then promotes the proliferation of fibroblasts in lung tissue. The study was published in the Respiratory Research journal.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by scarring of lung tissue that leads to shortness of breath and ultimately death. While IPF pathogenesis is far from completely understood, it is currently thought to occur due to the excessive deposition of extracellular matrix proteins (in response to lung epithelial cells damage). Transforming Growth Factor-beta (TGF-beta) is a major driver of fibrosis by inducing fibroblast proliferation (cells that synthesize the extracellular matrix) and collagen deposition, both key components of lung fibrosis.
The authors hypothesized that a specific gene – BARD1 (BRCA1-associated RING domain 1) – whose expression is increased and associated with a poor prognosis in lung cancer, might have a role in lung fibrosis. Previous findings reported that BARD1 is associated with TGF-beta expression, therefore supporting the teams’ hypothesis. The authors performed studies where they investigated how TGF-beta signaling affects BARD1 expression using several systems: in vitro culture of cells, mice with experimentally induced lung fibrosis (bleomycin-induced pulmonary fibrosis), and lung biopsies from pulmonary fibrosis patients.
The team discovered that the expression of both full-length BARD1 protein together with its isoform BARD1-beta, was upregulated in response to TGF-beta in epithelial cells and fibroblasts in vitro. The same increase in BARD1 and BARD1-beta proteins was detected in lung tissues from bleomycin-treated mice when compared to the control; and BARD1/BARD1-beta are expressed in fibrotic lung tissues and associated with disease progression in pulmonary fibrosis patients.
Authors suggest that BARD1 and BARD1-beta are downstream of TGF-beta signaling and may promote epithelial cell death and fibroblast proliferation. Since TGF-beta has multiple effects and has proven difficult to target therapeutically, authors note that their findings support the development of therapeutics targeting BARD1 as a potential therapy for lung fibrosis.