Porphyromonas gingivalis promotes malignancy and chemo-resistance via GSK3β-mediated mitochondrial oxidative phosphorylation in human esophageal squamous cell carcinoma

•GSK3β is a key regulator in the enhancement of the mtOXPHOS induced by Pg in ESCC cells;.•GSK3β is a key regulator in the malignancy and chemo-resistance induced by Pg in ESCC cells.•The effective removal of Pg and inhibition of its promotion of GSK3β-mediated mtOXPHOS can improve the prognosis of ESCC patients. Our prior studies have confirmed that long-term colonization of Porphyromonas gingivalis (Pg) and overexpression of the inflammatory factor glycogen synthase kinase 3β (GSK3β) promote the malignant evolution of esophageal squamous cell carcinoma (ESCC). We aimed to investigate the functional mechanism by which Pg could promote ESCC malignancy and chemo-resistance through GSK3β-mediated mitochondrial oxidative phosphorylation (mtOXPHOS), and the clinical implications. The effects of Pg and GSK3β on mtOXPHOS, malignant behaviors and response to paclitaxel and cisplatin treatment of ESCC cells were evaluated by in vitro and in vivo studies. The results showed that Pg induced high expression of the GSK3β protein in ESCC cells and promoted the progression and chemo-resistance via GSK3β-mediated mtOXPHOS in human ESCC. Then, Pg infection and the expression of GSK3β, SIRT1 and MRPS5 in ESCC tissues were detected, and the correlations between each index and postoperative survival of ESCC patients were analysed. The results showed that Pg-positive ESCC patients with high-expression of GSK3β, SIRT1 and MRPS5 have significant short postoperative survival. In conclusion, we demonstrated that the effective removal of Pg and inhibition of its promotion of GSK3β-mediated mtOXPHOS may provide a new strategy for ESCC treatment and new insights into the aetiology of ESCC.