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MiR-338* targeting smoothened to inhibit pulmonary fibrosis by epithelial-mesenchymal transition
Yi Zhuang1, Jinghong Dai2, Yongsheng Wang2
1Department of Medical Genetics, Nanjing University School of MedicineNanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of MedicineNanjing, China; Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing, China.
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. Recent studies indicate that some microRNAs (miRNAs) may play critical roles in the pathogenesis of pulmonary fibrosis. In this study, we aim to investigate whether miR-338* (miR-338-5p), which has been found to be associated with tumor progression, is associated with pathological process of pulmonary fibrosis. Balb/c mice were treated with bleomycin (BLM) to establish IPF models. Targtscan was used to predict the downstream target of miR-338*. Morphological changes were observed with light microscope and epithelial to mesenchymal transition (EMT) markers were detected by western blot. The expression of miR-338* or downstream target SMO was analyzed by real-time quantitative RT-PCR, northern blot or western blot. MiR-338* was down-regulated in the lung tissue from mice with bleomycin-induced pulmonary fibrosis. The smoothened (SMO) is a direct target of miR-338*, and knocking-down the expression of SMO could partially rescue the fibrotic phenotype of TGF-β-induced NuLi-1 cells. Over-expression of SMO led to the fibrotic phenotype of NuLi-1 cells even without TGF-β treatment. These findings showed that the over-expression of SMO contributed to the fibrotic phenotype of NuLi-1 cells by affecting the epithelial-to-mesenchymal transition (EMT) procedure. Furthermore, in vivo, lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. In conclusion, our results suggest that miR-338* can target SMO to reduce the EMT procedure and thus postpone the development of pulmonary fibrosis.
Insights
MicroRNA-338* (miR-338*) is reduced in pulmonary fibrosis. Targeting SMO with miR-338* can reduce epithelial-to-mesenchymal transition and slow lung fibrosis development.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- MicroRNA Research
Background:
- Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive lung injury, repair, and fibrosis.
- MicroRNAs (miRNAs) are increasingly recognized for their roles in the pathogenesis of fibrotic lung diseases.
Purpose of the Study:
- To investigate the role of miR-338* (miR-338-5p) in the pathological process of pulmonary fibrosis.
- To determine if miR-338* targets Smoothened (SMO) and influences epithelial-to-mesenchymal transition (EMT).
Main Methods:
- Established bleomycin (BLM)-induced pulmonary fibrosis models in Balb/c mice.
- Predicted miR-338* targets using TargetScan.
- Assessed morphological changes, EMT markers, and expression of miR-338* and SMO via microscopy, western blot, and RT-PCR.
Main Results:
- miR-338* expression was significantly down-regulated in BLM-induced pulmonary fibrosis lungs.
- SMO was identified as a direct target of miR-338*, and SMO knockdown partially rescued TGF-β-induced fibrosis in NuLi-1 cells.
- Overexpression of SMO promoted a fibrotic phenotype in NuLi-1 cells by inducing EMT; lentivirus-mediated miR-338* overexpression alleviated lung fibrosis in mice.
Conclusions:
- miR-338* targets SMO to inhibit EMT, thereby delaying the progression of pulmonary fibrosis.
- miR-338* represents a potential therapeutic target for managing lung fibrosis.
