Porphyromonas gingivalis extracellular vesicles promotes tumor metastasis in esophageal squamous cell carcinoma by inducing PRKACB/JNK/ NFATC2 axis

Porphyromonas gingivalis (Pg), a common oral microorganism linked to periodontal disease, has been recently shown to play a significant role in oral and systemic health through the secretion of extracellular vesicles (EVs). Nevertheless, the implications of Porphyromonas gingivalis-derived extracellular vesicles (Pg-EVs) on esophageal squamous cell carcinoma (ESCC) metastasis and the corresponding underlying mechanisms continue to be shrouded in ambiguity. Our study aimed to determine whether and how Pg-EVs mediate ESCC metastasis. Using 16sRNA gene sequencing, FISH and bioinformatics we found that Pg was abundant in human ESCC cancerous tissues and was associated with poor prognosis in ESCC patients. Our results further revealed that Pg-EVs enhanced the migration and invasion of cancer cells, promoted extravasation and metastasis by inducing NFATC2 expression both in vitro and in vivo. Mechanistically, we identified that Pg-EVs induced a new pattern recognition receptor PRKACB to activate the JNK pathway, resulting in the upregulation of NFATC2.Interestingly, the abundance of Pg in tumor tissues of EC patients was positively associated with the expression levels of PRKACB and NFATC2. Moreover, high expression of PRKACB or NFATC2 was significantly associated with a shorter overall survival time of EC patients. Our findings suggest that Pg is highly prevalent in ESCC, and it is associated with poor prognosis, stage, and lymph node metastasis. As a consequence of increasing PRKACB expression, Pg-EVs activate the JNK pathway, resulting in an increase in NFATC2 expression.