Dataset Information

MicroRNA?375 prevents TGF???dependent transdifferentiation of lung fibroblasts via the MAP2K6/P38 pathway.

ABSTRACT: Transdifferentiation of lung fibroblasts to myofibroblasts is a crucial pathophysiological process in pulmonary fibrosis. MicroRNA?375 (miR?375) was initially identified as a tumor?suppressive factor, and its expression was negatively associated with the severity of lung cancer; however, its role and potential mechanism in myofibroblast transdifferentiation and pulmonary fibrosis remain unclear. In the present study, human lung fibroblasts were stimulated with transforming growth factor?? (TGF??) to induce myofibroblast transdifferentiation. A mimic and inhibitor of miR?375, and their negative controls, were used to overexpress or suppress miR?375 in lung fibroblasts, respectively. The mRNA expression levels of fibrotic markers, and protein expression of ??smooth muscle actin and periostin, were subsequently detected by reverse transcription?quantitative PCR and western blotting, to assess myofibroblast transdifferentiation. miR?375 was markedly upregulated in human lung fibroblasts after TGF?? stimulation. The miR?375 mimic alleviated, whereas the miR?375 inhibitor aggravated TGF???dependent transdifferentiation of lung fibroblasts. Mechanistically, miR?375 prevented myofibroblast transdifferentiation and collagen synthesis by blocking the P38 mitogen?activated protein kinases (P38) pathway, and P38 suppression abrogated the deleterious effect of the miR?375 inhibitor on myofibroblast transdifferentiation. Furthermore, the present study revealed that mitogen?activated protein kinase kinase 6 was involved in P38 inactivation by miR?375. In conclusion, miR?375 was implicated in modulating TGF???dependent transdifferentiation of lung fibroblasts, and targeting miR?375 expression may help to develop therapeutic approaches for treating pulmonary fibrosis.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7411355 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MicroRNA‑375 prevents TGF‑β‑dependent transdifferentiation of lung fibroblasts via the MAP2K6/P38 pathway.

Zhang Xinghua X Chen Qian Q Song Hengya H Jiang Wanli W Xie Songping S Huang Jie J Kang Ganjun G

Molecular medicine reports 20200622 3

Transdifferentiation of lung fibroblasts to myofibroblasts is a crucial pathophysiological process in pulmonary fibrosis. MicroRNA‑375 (miR‑375) was initially identified as a tumor‑suppressive factor, and its expression was negatively associated with the severity of lung cancer; however, its role and potential mechanism in myofibroblast transdifferentiation and pulmonary fibrosis remain unclear. In the present study, human lung fibroblasts were stimulated with transforming growth factor‑β (TGF‑β ...[more]

PMID: 32582987

Similar Datasets

Project description:Aerobic glycolysis has been shown to contribute to the abnormal activation of lung fibroblasts with excessive collagen deposition in lipopolysaccharide (LPS)-induced pulmonary fibrosis. Targeting aerobic glycolysis in lung fibroblasts might therefore be considered as a promising therapeutic approach for LPS-induced pulmonary fibrosis. In the present study, the aim was to investigate whether metformin, a widely used agent for treating type 2 diabetes, could alleviate LPS-induced lung fibroblast collagen synthesis and its potential underlying mechanisms. Different concentrations of metformin were used to treat the human lung fibroblast MRC-5 cells after LPS challenge. Indicators of aerobic glycolysis in MRC-5 cells were detected by measuring glucose consumption and lactate levels in culture medium in addition to lactate dehydrogenase activity in cellular lysates. The glucose consumption, lactate levels and the lactate dehydrogenase activity were measured respectively using colorimetric/fluorometric and ELISA kits. The effects of metformin in AMP-activated protein kinase (AMPK) activation was assessed by mitochondrial complex I activity kits. Collagen I, α-smooth muscle actin (α-SMA) and collagen III were used as markers of collagen synthesis, which was measured using western blotting, whereas phosphorylated (p-) AMPK, AMPK, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and mTOR were detected by western blotting. Metformin significantly decreased mitochondrial complex I activity and upregulated the expression of p-AMPK/AMPK protein in a concentration-dependent manner. Furthermore, the aerobic glycolysis mediated by PFKFB3 and collagen synthesis in LPS-treated MRC-5 cells was gradually inhibited with increasing concentrations of metformin. However, this inhibitory role of metformin on PFKFB3-meditaed aerobic glycolysis and collagen synthesis was prevented by treatments with 3BDO and compound C, which are specific mTOR activator and AMPK inhibitor, respectively. Taken together, the findings from this study suggested that metformin may prevent PFKFB3-associated aerobic glycolysis from enhancing collagen synthesis in lung fibroblasts via regulating the AMPK/mTOR pathway.

Dataset Information

MicroRNA?375 prevents TGF???dependent transdifferentiation of lung fibroblasts via the MAP2K6/P38 pathway.

Publications

MicroRNA‑375 prevents TGF‑β‑dependent transdifferentiation of lung fibroblasts via the MAP2K6/P38 pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets