Abstract: Objective To elucidate the mechanism by which Porphyromonas gingivalis(Pg)promotes the progression of esophageal squamous cell carcinoma(ESCC)through TAGLN2-mediated activation of the YAP/TAZ-ERK axis. Methods Immunohistochemistry was performed to evaluate Pg abundance and TAGLN2 protein expression in 60 ESCC specimens,and the correlation between them was analyzed.ESCC cells were subjected to Pg infection or siTAGLN2 treatment,followed by RNA sequencing to identify Pg- and TAGLN2-related differentially expressed genes and to define a Pg-TAGLN2 gene signature.Transcriptomic and proteomic data from publicly available databases,including GSE53625,TCGA-ESCA,and published proteomic datasets,were integrated for functional enrichment analysis and evaluation of the clinical relevance of the Pg-TAGLN2 gene signature.Western blotting was used to detect the expression of p-ERK/ERK,p-YAP/YAP,p-TAZ/TAZ,RASA1,and F-actin in ESCC cells after Pg infection,TAGLN2 knockdown,or TAGLN2 overexpression.Immunofluorescence assays were performed to examine the subcellular localization of YAP/TAZ in ESCC cells under different treatment conditions.Transwell assays were used to assess cell migration and invasion,and CCK-8 assays were conducted to evaluate cell proliferation. Results Pg abundance was positively correlated with TAGLN2 protein expression in ESCC tissues,and high TAGLN2 expression was associated with poor prognosis in patients with ESCC.A total of 55 Pg-induced differentially expressed genes and 8 Pg-TAGLN2 signature genes were significantly enriched in the MAPK/ERK signaling pathway.In public transcriptomic and proteomic datasets,higher GSVA scores for the Pg-TAGLN2 gene signature were associated with unfavorable prognosis in ESCC patients.Pg infection significantly increased p-ERK levels in ESCC cells.TAGLN2 knockdown reduced p-ERK levels and attenuated Pg-induced ERK activation.Meanwhile,TAGLN2 knockdown increased p-YAP and p-TAZ levels while decreasing YAP and TAZ expression.In contrast,TAGLN2 overexpression produced the opposite changes.Moreover,TAGLN2 knockdown promoted the cytoplasmic retention of YAP/TAZ and reduced their nuclear localization.In TAGLN2-overexpressing ESCC cells,YAP/TAZ knockdown markedly attenuated the promotive effects of TAGLN2 overexpression on cell proliferation,migration,and invasion. Conclusion Pg infection induces upregulation of TAGLN2 in ESCC,thereby activating the YAP/TAZ-ERK signaling axis and promoting ESCC progression.Targeting the RAS-ERK signaling pathway may represent a potential therapeutic strategy for Pg-associated ESCC.

Key words: esophageal squamous cell carcinoma, Porphyromonas gingivalis, TAGLN2, YAP/TAZ, MAPK/ERK