CircRNA TADA2A relieves idiopathic pulmonary fibrosis by inhibiting proliferation and activation of fibroblasts

Juan Li,Pan Qin,Wei Zhao,Guojun Zhang,Ping Li,Da Zhang

doi:10.1038/s41419-020-02747-9

Juan Li, Pan Qin + Show 4 more

Open Access

https://doi.org/10.1038/s41419-020-02747-9

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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.

Highlights

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease, with high morbidity and lacking medical therapies to improve the survival rate
CircTADA2A was downregulated in idiopathic pulmonary fibrosis (IPF) lung fibroblasts Li et al.[5] identified 67 circRNAs, which were significantly dysregulated in the blood samples of patients with IPF
The results of qRT-PCR and fluorescence in situ hybridization (FISH) depicted that circTADA2A was mainly located in the cytoplasm and the abundance of circTADA2A was lower in human IPF fibroblastic cell lines than that of the normal human fibroblastic cell line (Fig. 1b)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease, with high morbidity and lacking medical therapies to improve the survival rate. The representative characteristic of IPF is the abundant deposition of extracellular matrix (ECM) in the alveolar parenchyma, which will sequentially irreversible alters normal lung architecture and resulting in respiratory failure[1]. As a major producer of ECM, the significant role of activated fibroblasts in the development of IPF is apparent. Fibroblasts serve a crucial role in tissue remodeling and fibrosis. In normal wound healing, activated fibroblasts secrete. ECM to provide a scaffold for the restoration of normal lung architecture and eventually undergo apoptosis to restrain the excessive production of ECM2. In the lung tissues of patients with IPF, fibroblasts present several dysfunctions, including the apoptosis resistance, inundant proliferation, and sustained activation[3], which lead to the massive accumulation of ECM and given rise to fibrosis

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