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The CDR1as/miR-7/TGFBR2 Axis Modulates EMT in Silica-Induced Pulmonary Fibrosis
1Department of Occupational Medicine and Environmental Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Abstract:
Silicosis is one of the typical forms of pneumoconiosis characterized by abnormal proliferation of fibroblasts and deposition of extracellular matrix. Recent findings have shown that microRNAs and circular RNAs (circRNAs) are implicated in many diseases. However, the function of noncoding RNAs in pulmonary fibrosis remain to be elucidated. Here, miR-7 was found significantly decreased in silica-treated pulmonary epithelial cells as well as in fibrotic lung tissues of mice. Elevated expression of miR-7 via agomir injection relieved lung fibrosis in vivo. Further molecular study showed that miR-7 played its role against pulmonary fibrosis by blocking epithelial-mesenchymal transition (EMT) progression of human bronchial epithelial cells and A549 cells. Notably, transforming growth factor beta receptor 2 (TGFBR2) was identified as a target gene of miR-7 with bioinformatics tools, which was verified by dual luciferase receptor gene assay in human bronchial epithelial cells and A549 cells. Silica induced elevation of TGFBR2 could be abolished by exogenous expression of miR-7. Furthermore, bioinformatics software indicated that circRNA CDR1as had several binding sites for miR-7. The inhibitory effects of miR-7 on EMT and its target TGFBR2 were suppressed by circRNA CDR1as, which contributed to pulmonary fibrosis. Our studies also revealed overexpressed miR-7 could repress fibrogenesis of lung fibroblasts induced by TGF-β1. Collectively, circRNA CDR1as stimulated by silica could sponge miR-7 to release TGFBR2, plays an important role during pulmonary fibrosis by promoting EMT process. These results indicated that the interaction between miR-7 and circRNA CDR1as may exert important functions and provide potential therapeutic targets in lung fibrotic diseases.
Insights
Silica exposure decreases miR-7, a microRNA that combats pulmonary fibrosis by inhibiting epithelial-mesenchymal transition (EMT). Restoring miR-7 levels alleviates lung fibrosis, suggesting a therapeutic target for fibrotic lung diseases.
Area of Science:
- Molecular Biology
- Cell Biology
- Pulmonary Medicine
Background:
- Silicosis, a form of pneumoconiosis, involves fibroblast proliferation and extracellular matrix deposition.
- MicroRNAs (miRNAs) and circular RNAs (circRNAs) are increasingly recognized for their roles in various diseases.
- The specific functions of noncoding RNAs in pulmonary fibrosis are not fully understood.
Purpose of the Study:
- To investigate the role of noncoding RNAs, specifically miR-7 and circRNA CDR1as, in silica-induced pulmonary fibrosis.
- To elucidate the molecular mechanisms by which these noncoding RNAs regulate epithelial-mesenchymal transition (EMT) and fibrogenesis.
- To explore the potential of targeting the miR-7/circRNA CDR1as interaction for therapeutic interventions in lung fibrotic diseases.
Main Methods:
- Quantitative analysis of miR-7 and TGFBR2 expression in silica-treated cells and fibrotic lung tissues.
- In vivo studies using agomir injections to elevate miR-7 levels and assess effects on lung fibrosis.
- Molecular assays including dual luciferase reporter gene assays to confirm target interactions.
- Bioinformatics analysis to predict and validate binding sites between miR-7 and circRNA CDR1as.
Main Results:
- miR-7 expression was significantly reduced in silica-exposed cells and fibrotic lung tissues.
- Overexpression of miR-7 ameliorated lung fibrosis in vivo and inhibited EMT in lung epithelial cells.
- Transforming growth factor beta receptor 2 (TGFBR2) was identified as a direct target of miR-7.
- circRNA CDR1as was found to sponge miR-7, thereby promoting EMT and TGFBR2 expression, contributing to pulmonary fibrosis.
Conclusions:
- Silica-induced circRNA CDR1as sponges miR-7, leading to increased TGFBR2 expression and promoting EMT, which drives pulmonary fibrosis.
- miR-7 acts as a tumor suppressor in pulmonary fibrosis by inhibiting EMT and fibrogenesis.
- The interaction between miR-7 and circRNA CDR1as presents a potential therapeutic strategy for treating lung fibrotic diseases.
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