Autophagic tumor-associated macrophages promote the endothelial mesenchymal transition in lung adenocarcinomas through the FUT4/p-ezrin pathway

BACKGROUND: Lung adenocarcinoma is one of the most common malignant tumors with high morbidity and mortality, but the effect of Tumor-associated macrophages (TAMs) on lung adenocarcinoma has not been studied clearly now. METHODS: In this study, TAMs were stably transfected with Atg5 silence or overexpression lentiviral vectors to inhibit or induce autophagy of TAMs. In addition, the expression of fucosyltransferase IV (FUT4) or Ezrin were interfered in TAMs with autophagy. The above treated TAMs were then co-cultured with A549 or H1299 cells. The expressions of genes were detected by qPCR, western blotting, cell immunofluorescence, and enzyme-linked immunosorbent assay. Meanwhile, cell migration and invasion were analyzed by Transwell assay and wound healing assay. Furthermore, the effects of TAMs with autophagy were explored in lung adenocarcinoma xenograft model of mice. RESULTS: The results showed that overexpression of autophagy-related gene 5 (ATG5) induced autophagy in TAMs, which increased the expression of FUT4, TGF-β1, and p-ezrin, and promoted epithelial-mesenchymal transition (EMT) in lung adenocarcinoma cells. However, FUT4 silencing partially reversed the effects of TAM autophagy, specifically, the expression of TGF-β1 and p-ezrin was inhibited and EMT in lung adenocarcinoma cells was suppressed. Notably, ezrin deletion in autophagic TAMs induced by rapamycin reduced TGF-β1 expression and suppressed EMT in lung adenocarcinoma cells. Consistently, in vivo experiments also revealed that autophagic TAMs increased the expression of FUT4, TGF-β1, and p-ezrin, and promoted EMT in lung adenocarcinomas. Similarly, FUT4 silencing partially reversed the effects of autophagic TAMs on EMT in lung adenocarcinomas. CONCLUSIONS: In conclusion, autophagic TAMs promoted TGF-β1 secretion through the FUT4/p-ezrin pathway and induced EMT in co-cultured lung adenocarcinoma cells.