Abstract
The excessive activation and proliferation of lung fibroblasts are responsible for the abundant deposition of extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF), while its specific mechanism is still unknown. This study focuses on the role of circRNA (circ) TADA2A in functional abnormalities of lung fibroblasts and aims to elaborate its regulatory mechanism. In the present study, circTADA2A was downregulated in both IPF primary human lung fibroblasts and human IPF fibroblastic cell lines. Functionally, the overexpression of circTADA2A repressed the activation and proliferation of normal human fibroblastic cell line induced by several fibrogenic growth factors. Using fluorescence in situ hybridization (FISH), luciferase reporter assays, and RNA pull-down, circTADA2A was confirmed to function as sponges of miR-526b and miR-203, thus releasing the expression of Caveolin (Cav)-1 and Cav2. The overexpression of circTADA2A suppressed lung-fibroblasts activation via Cav1 and reduced lung-fibroblasts proliferation via Cav2. In vivo experiments also confirmed that the overexpression of circTADA2A decreased fibrogenic responses induced by bleomycin in lung-fibrosis mice. Collectively, circTADA2A repressed lung-fibroblasts activation via miR-526b/Cav1 and reduced lung-fibroblasts proliferation via miR-203/Cav2, thus inhibiting the excessive deposition of ECM and relieving IPF.