Porphyromonas gingivalis promotes oral squamous cell carcinoma progression via the IL-6/EZH2/Snai2 axis

Oral squamous cell carcinoma (OSCC) is a common malignancy with poor prognosis. Chronic infection with Porphyromonas gingivalis (P.g.) has been implicated in OSCC progression, but the molecular mechanisms underlying P.g.-induced tumor invasion and metastasis remain incompletely understood. ELISA, flow cytometry, proliferation assay and migration assay, were conducted on OSCC primary cells and the HSC-2 cell line under P.g. infection or IL-6 stimulation. Zeste homologue 2 (EZH2) and Snai2 were modulated via overexpression, knockdown, and inhibitor treatments, to evaluate the role of EZH2 and Snai2 in the regulation of OSCC phenotypes. The relationships between Snai2 and epithelial-mesenchymal transition (EMT) was analyzed using GSEA, differential expression, and KEGG pathway enrichment. For in vitro assay, P.g. infection significantly increased IL-6 levels in the oral microenvironment. IL-6 upregulation promoted OSCC cell proliferation and migration by enhancing EZH2 and Snai2 expression. EZH2 overexpression increased Snai2 transcription and OSCC malignancy, whereas EZH2 siRNA/inhibitor or Snai2 siRNA attenuated these effects. In bioinformatic analysis results, DEG and survival analysis showed the higher expression of Snai2 in OSCC patientsꞌ group and the negative relevance of survival probability with Snai2 expression, respectively. KEGG enrichment and PPI analysis indicated the relationships among EZH2 or Snai2 expression, EMT and infection-related signaling pathways. Our study revealed a novel IL-6/EZH2/Snai2 signaling axis, which connected the P.g. infection, IL-6 upregulation, abnormal expression of EZH2 and Snai2, and OSCC progression. This study filled the gap of molecular mechanisms underlying P.g.-induced OSCC invasion and metastasis, providing a potential therapeutic target for inhibiting OSCC progression.