MicroRNA‑375 prevents TGF‑β‑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-β (TGF-β) 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 α-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-β stimulation. The miR-375 mimic alleviated, whereas the miR-375 inhibitor aggravated TGF-β-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-β-dependent transdifferentiation of lung fibroblasts, and targeting miR-375 expression may help to develop therapeutic approaches for treating pulmonary fibrosis.

Therapeutic and diagnostic targeting of fibrosis in metabolic, proliferative and viral disorders

“…Inhibition of mRNA targets in these pathways has also been investigated as an anti-fibrotic therapy strategy. For example, the TGF-β-induced activation of the p38 MAPK pathway was regulated via inhibition of the MAP2K6 mRNA by a miR-375 (i.e., a cancer-suppressive microRNA [90]) mimetic, preventing lung fibroblast activation [91]. This study exemplifies the anti-fibrotic potential of microRNAs [92].…”

Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer

“…1A ). Neither TGFβ nor Wnt signaling induced MenaINV expression in human triple negative breast cancer cells MDA-MB-231 (231) in response to increasing doses of TGFβ and LiCl, activators of TGFβ and Wnt signaling, respectively(40, 41) ( Supp Fig. 1B &C ).…”

miR‑3613‑3p/MAP3K2/p38/caspase‑3 pathway regulates the heat‑stress‑induced apoptosis of endothelial cells

“…In this study, phosphorylation of p38 was at a high level 2 h after HS, coinciding with the decrease in miR-3613-3p and increase in MAP3K2 expression. p38 MAPK is a downstream molecule of multiple signalling pathways, and is eventually activated through signalling pathways composed of extracellular signalling molecules, specific receptors on the surface of the membrane and intracellular signalling molecules (45)(46)(47). Notably, the initiation time and duration of p38 MAPK activation are irregular and may vary with different cell types or environmental stresses.…”