FOXO3 regulates Smad3 and Smad7 through SPON1 circular RNA to inhibit idiopathic pulmonary fibrosis

Abstract

Forkhead box protein O3 (FOXO3) has good inhibition ability toward fibroblast activation and extracellular matrix, especially for the treatment of idiopathic pulmonary fibrosis. How FOXO3 regulates pulmonary fibrosis remains unclear. In this study, we reported that FOXO3 had binding sequences with F-spondin 1 (SPON1) promoter, which can activate its transcription and selectively promote the expression of SPON1 circRNA (circSPON1) but not mRNA expression. We further demonstrated that circSPON1 was involved in the extracellular matrix deposition of HFL1. In the cytoplasm, circSPON1 directly interacted with TGF-β1-induced Smad3 and inhibited the activation of fibroblasts by inhibiting nuclear translocation. Moreover, circSPON1 bound to miR-942-5p and miR-520f-3p that interfered with Smad7 mRNA and promoted Smad7 expression. This study revealed the mechanism of FOXO3-regulated circSPON1 in the development of pulmonary fibrosis. Potential therapeutic targets and new insights into the diagnosis and treatment of idiopathic pulmonary fibrosis based on circRNA were also provided.

Exosomal circRNAs in the plasma serve as novel biomarkers for IPF diagnosis and progression prediction

“…Several studies have demonstrated the critical role of circRNAs in the development and progression of IPF [ 7 – 9 , 12 , 13 ]. For example, Zhang et al found that circHIPK3 could promote lung fibroblast-to-myofibroblast transition by acting as a competing endogenous RNA of miR-338-3p, leading to increased SOX4 and COL1A1 expression [ 20 ].…”

“…Xu et al reported that circANKRD42 could sponge miR-324-5p and miR-136-5p to promote YAP1 translation into the nucleus during IPF [ 13 ]. Additionally, Li et al revealed that circSPON1 bound to miR-942-5p and miR-520f-3p, interfering with Smad7 mRNA and promoting Smad7 expression in the development of pulmonary fibrosis [ 7 ]. In our study, we found that hsa_circ_0044226 was positively associated with the lung function of IPF patients and upregulated in AE-IPF patients.…”

“…CircRNAs are a novel class of noncoding RNA with a unique covalent loop structure that provides them with unusual stability [ 4 , 6 ]. They have been found to interact with proteins, microRNAs, and can even be translated into peptides or proteins, playing a role in various human diseases [ 6 ] including idiopathic pulmonary fibrosisetc [ 7 – 13 ]. However, there is currently no research on the function and application of exosomal circRNAs in idiopathic pulmonary fibrosis (IPF).…”

Circular RNAs and their roles in idiopathic pulmonary fibrosis

“…CircSPON1 generated from F-spondin 1 (SPON1) under the influence of forkhead box O3 (FOXO3) is involved in pulmonary fibrosis through the suppression of fibroblast activation by inhibiting the translocation of SMAD-3 into the nucleus. CircSPON1 also acts as a sponge for miR-942-5p and miR-520f-3p and increases the expression of SMAD-7 which regulates TGF-β signaling negatively [ 129 ]. Signal transducer and activator of transcription 3 (STAT-3) and zinc finger protein (Gli-2) are pro-fibrotic molecules which are involved in pulmonary fibrosis, and it was found that circRNA-662 and circRNA-949 have sponge like activity against miR-29b which interacts with STAT-3 and Gli-2.…”