Irradiated Human Umbilical Vein Endothelial Cells Undergo Endothelial-Mesenchymal Transition via the Snail/miR-199a-5p Axis to Promote the Differentiation of Fibroblasts into Myofibroblasts

Abstract

Radiation induced pulmonary fibrosis (RIPF) is one of the major side effects of radiotherapy for lung cancer. Previous studies have shown that endothelial cells and activated myofibroblasts play a key role in RIPF. However, the interaction between irradiated endothelial cells and activation of myofibroblasts has not been reported. The aim of the present study was to examine whether irradiated endothelial cells would affect the differentiation of fibroblasts into myofibroblasts in the process of RIPF. In the current study, we used a coculture system that allowed direct contact between human fetal lung fibroblasts (MRC-5) and irradiated human umbilical vein endothelial cells (HUVECs). After 24 or 48 h, cells were sorted by flow cytometry. Radiation induced endothelial-mesenchymal transition (EndMT) by significantly increasing the expression of Snail and vimentin and reducing the expression of CD31 in HUVECs. In addition, irradiation of HUVECs induced the expression of collagen type I and α-smooth muscle actin (α-SMA) in MRC-5 cells. Further investigation indicated that irradiation of HUVECs induced the differentiation of fibroblasts into myofibroblasts through the Snail/miR-199a-5p axis. We conclude that irradiated endothelial cells undergo EndMT to promote differentiation of fibroblasts into myofibroblasts via the Snail/miR-199a-5p axis.

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

“…In irradiated human pulmonary artery ECs, EndMT was dependent on HIF-1α expression via TGF-βR1/Smad signaling. Data generated in that study revealed HIF-1α-related EndMT in human RIPF tissues 95 . A recent study provided evidence that in a coculture system of human fetal lung fibroblasts (MRC-5) and irradiated HUVECs, Snail and vimentin expression was upregulated, and CD31 expression was downregulated.…”

“…A recent study provided evidence that in a coculture system of human fetal lung fibroblasts (MRC-5) and irradiated HUVECs, Snail and vimentin expression was upregulated, and CD31 expression was downregulated. Radiation-induced EndMT enhances the differentiation of fibroblasts to myofibroblasts via the Snail/ miR-199a-5p axis (Table 2) 95 .…”

Interplay among SNAIL Transcription Factor, MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Regulation of Tumor Growth and Metastasis

“…In rhabdomyosarcoma, SNAIL regulates the expression of myogenic-associated miRNAs, such as miR-1, miR-206, and miR-378 [14]. What is more, the SNAIL/miR-199a-5p axis promotes the differentiation of fibroblasts into myofibroblasts by the induction of endothelial-mesenchymal transition [162].…”

Fusobacterium nucleatumfacilitates cetuximab resistance in colorectal cancer via the PI3K/AKT and JAK/STAT3 pathways

“…Total cell proteins were extracted after treatment with medium (control) and Fn at appointed time. The assays were carried out as previously described 47 . The target proteins were detected with primary antibodies recognizing AKT (Cell Signaling Technology, CST #9272; 1:1,000), p-AKT (CST #4060; 1:2,000), STAT3 (CST #9139; 1:1,000), and p-STAT3 (CST #9145; 1:2,000).…”