Colonization by Porphyromonas gingivalis in cervical squamous cell carcinomas promotes metastasis through FimA/CD151/ITGB1 signaling

Abstract Background Cervicovaginal microbiota dysbiosis has been implicated in the progression of cervical cancer. Recent studies have reported an increased abundance of Porphyromonas species in the vaginal microbiota of cervical cancer patients. Porphyromonas gingivalis (P. gingivalis), a key periodontal pathogen, has been associated with adverse pregnancy outcomes and bacterial vaginosis; however, its potential role in the progression of cervical squamous cell carcinoma (CSCC) remains largely unexplored. Methods We employed immunohistochemistry (IHC), 16S rRNA fluorescence in situ hybridization (FISH), and immunofluorescence to detect P. gingivalis in CSCC tissues. The association between P. gingivalis colonization and CSCC patient survival outcomes was assessed. Transwell and wound healing assays were used to assess the migration and invasion abilities of CSCC cells. In vivo xenograft mouse models were established to evaluate the impact of P. gingivalis on tumor growth and metastasis. Pull-down assays were employed to investigate interactions between the P. gingivalis fimbrial protein FimA and host cell membrane proteins. RNA sequencing and Western blotting were utilized to identify signaling pathways activated by P. gingivalis in host cells. Results Porphyromonas gingivalis was detected immunohistochemically in 63% of CSCC tumor tissues, with significantly higher colonization in tumors compared to adjacent nontumor tissues (P < 0.0001). The presence of P. gingivalis was significantly associated with advanced tumor stage (P < 0.01), distant metastasis (P < 0.05), lymph node metastasis (P < 0.01), and poor survival outcomes (P = 0.0257, HR = 3.167) in CSCC patients. P. gingivalis preferentially adhered to CSCC cells and promoted cell migration and invasion. In this study, animal models revealed that P. gingivalis promoted lung and lymph node metastasis in CSCC without affecting tumor growth. Pull-down assays revealed that FimA interacts with CD151 and integrin β1 (ITGB1), which are highly expressed in CSCC cells. Knockdown of CD151 and ITGB1 significantly reduced P. gingivalis adhesion to CSCC cells (P < 0.01) and suppressed its effects on cell migration and invasion (P< 0.05). P. gingivalis treatment activated the JNK/paxillin pathway and triggered actin cytoskeleton reorganization. Conclusion This study identifies P. gingivalis as a tumor-associated bacterium that promotes CSCC metastasis through direct interaction between its fimbrial adhesin FimA and the host CD151/ITGB1 complex. This interaction activates JNK/paxillin signaling, induces cytoskeletal reorganization, and enhances the metastatic capacity of CSCC cells. Targeting this microbial-host interaction may provide a novel therapeutic intervention for P. gingivalis-driven CSCC metastasis.