牙龈卟啉单胞菌通过GARP促进TGF-β/SMAD轴介导食管鳞状细胞癌细胞的上皮间质转化OA北大核心CSTPCD

Objective:To elucidate the molecular mechanism by which Porphyromonas gingivalis(Pg)induces epithelial-mesenchymal transition(EMT)in esophageal squamous cell carcinoma(ESCC)cells.Methods:KEGG was used to identify the biological pathways enriched by Pg-induced differentially expressed genes in ESCC.WB and/or immunofluorescence(IF)were used to detect the changes in the expression of glycoprotein-A repetitions predominant protein(GARP),TGF-β,pSMAD/SMAD,Snail,Oct4 and EMT-related molecules in Pg-induced ESCC cells.ELISA was used to measure changes in TGF-β1 level.Immunohistochemistry was used to detect the expression of GARP and TGF-β1 in ESCC tissues.The tumorigenic effect of Pg on ESCC was verified by Transwell assays and animal experiments.Results:Pg activated multiple signaling pathways,such as TGF-β,Hippo,and PI3K/Akt.Pg-infection stimulated an increased secretion of total TGF-β1 and active TFG-β1 in ESCC cells(P<0.01),leading to SMAD2/3 phosphorylation and nuclear translocation,which induced increased protein expression of N-cadherin,Snail,and Oct4 and decreased E-cadherin.These alterations collectively promoted the migration and invasion of ESCC cells and the growth of subcutaneous tumor in nude mice(all P<0.01).Silencing GARP expression in ESCC cells reversed the phenotypic changes induced by Pg.The protein levels of TGF-β1 and GARP in ESCC tissues with high Pg abundance were higher than those in ESCC tissues with low Pg abundance.The abundance of Pg was positively correlated with the protein expression of TGF-β1 and GARP(P=0.001 5).Conclusion:Pg activates the TGF-β/Smad axis through GARP to promote the occurrence of EMT in ESCC cells,thereby facilitating the migration,invasion and growth of ESCC cells.Pg clearance or TGF-β signaling blockade can reverse these Pg-induced promotive effects on ESCC.