FBXL16 inhibits transdifferentiation of lung fibroblasts. MRC-5 were treated with 2 ng/mL TGF-β for 72 h.
MiR-1307-5p enhances fibroblast transdifferentiation to exacerbate chronic obstructive pulmonary disease through regulating FBXL16/HIF1α axis
Paper
2024
Respiratory Research |
DOI
Background
Chronic obstructive pulmonary disease (COPD) is an irreversible progressive lung disease. This study identified significantly increased miR-1307-5p expression in lung fibroblasts from COPD patients. Functionally, miR-1307-5p promotes TGF-β-induced fibroblast activation and transdifferentiation into myofibroblasts. It directly targets FBXL16, reducing its expression and triggering HIF1α stabilization. Silencing FBXL16 mimics miR-1307-5p effects, whereas restoring FBXL16 reverses them. In mice, miR-1307-5p overexpression worsens cigarette-smoke-induced COPD pathology, while FBXL16 replenishment alleviates emphysema, inflammation, and lung dysfunction. These findings reveal an important miR-1307-5p/FBXL16/HIF1α axis in COPD and suggest miR-1307-5p as a potential therapeutic target.
Key Findings
Key findings include: 1) miR-1307-5p is significantly elevated in lung fibroblasts and blood of COPD patients. 2) Overexpression in a chronic cigarette-smoke mouse model aggravates pulmonary inflammation, emphysema, and lung function decline, while FBXL16 delivery attenuates these effects. 3) miR-1307-5p promotes TGF-β-induced myofibroblast differentiation with increased α-SMA, calponin, collagen I and fibronectin; inhibition suppresses it. 4) FBXL16 is a direct target verified by 3'-UTR luciferase assays; FBXL16 knockdown mimics whereas its overexpression blocks fibroblast transdifferentiation. 5) Mechanistically, miR-1307-5p suppresses FBXL16 leading to HIF1α protein stabilization, which enhances fibroblast activation. Co-expression of FBXL16 reduces HIF1α and abrogates the pro-fibrotic effects. Thus, the miR-1307-5p/FBXL16/HIF1α axis is critical for COPD progression and a promising therapeutic target.
Contribution
Creative Biogene provided the FBXL16 miRNA 3'-UTR reporter construct (pMirTarget) used in luciferase experiments to validate direct targeting by miR-1307-5p.
Chronic obstructive pulmonary disease (COPD) is an irreversible progressive lung disease. This study identified significantly increased miR-1307-5p expression in lung fibroblasts from COPD patients. Functionally, miR-1307-5p promotes TGF-β-induced fibroblast activation and transdifferentiation into myofibroblasts. It directly targets FBXL16, reducing its expression and triggering HIF1α stabilization. Silencing FBXL16 mimics miR-1307-5p effects, whereas restoring FBXL16 reverses them. In mice, miR-1307-5p overexpression worsens cigarette-smoke-induced COPD pathology, while FBXL16 replenishment alleviates emphysema, inflammation, and lung dysfunction. These findings reveal an important miR-1307-5p/FBXL16/HIF1α axis in COPD and suggest miR-1307-5p as a potential therapeutic target.
Key Findings
Key findings include: 1) miR-1307-5p is significantly elevated in lung fibroblasts and blood of COPD patients. 2) Overexpression in a chronic cigarette-smoke mouse model aggravates pulmonary inflammation, emphysema, and lung function decline, while FBXL16 delivery attenuates these effects. 3) miR-1307-5p promotes TGF-β-induced myofibroblast differentiation with increased α-SMA, calponin, collagen I and fibronectin; inhibition suppresses it. 4) FBXL16 is a direct target verified by 3'-UTR luciferase assays; FBXL16 knockdown mimics whereas its overexpression blocks fibroblast transdifferentiation. 5) Mechanistically, miR-1307-5p suppresses FBXL16 leading to HIF1α protein stabilization, which enhances fibroblast activation. Co-expression of FBXL16 reduces HIF1α and abrogates the pro-fibrotic effects. Thus, the miR-1307-5p/FBXL16/HIF1α axis is critical for COPD progression and a promising therapeutic target.
Contribution
Creative Biogene provided the FBXL16 miRNA 3'-UTR reporter construct (pMirTarget) used in luciferase experiments to validate direct targeting by miR-1307-5p.