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

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-beta (TGF-beta) to induce myofibroblast transdifferentiation. A mimic and inhibitor ofmiR-375, and their negative controls, were used to overexpress or suppressmiR-375in lung fibroblasts, respectively. The mRNA expression levels of fibrotic markers, and protein expression of alpha-smooth muscle actin and periostin, were subsequently detected by reverse transcription-quantitative PCR and western blotting, to assess myofibroblast transdifferentiation.miR-375was markedly upregulated in human lung fibroblasts after TGF-beta stimulation. ThemiR-375mimic alleviated, whereas themiR-375inhibitor aggravated TGF-beta-dependent transdifferentiation of lung fibroblasts. Mechanistically,miR-375prevented myofibroblast transdifferentiation and collagen synthesis by blocking theP38mitogen-activated protein kinases (P38) pathway, and P38 suppression abrogated the deleterious effect of themiR-375inhibitor on myofibroblast transdifferentiation. Furthermore, the present study revealed that mitogen-activated protein kinase kinase 6 was involved in P38 inactivation bymiR-375. In conclusion,miR-375was implicated in modulating TGF-beta-dependent transdifferentiation of lung fibroblasts, and targetingmiR-375expression may help to develop therapeutic approaches for treating pulmonary fibrosis.