Mediator Complex Subunit 27-Enriched Small Extracellular Vesicles Mediate the Crosstalk between Periodontal Bacteria and HPV-Driven Head and Neck Cancer

It is well-documented in the literature that two well-known periodontal bacteria, <i>Fusobacterium nucleatum</i> and <i>Porphyromonas gingivalis</i>, play a pivotal role in regulating the cancer stemness properties of head and neck cancer (HNC); however, their role in human papillomavirus-driven HNC (HPV-driven HNC) remains unexplored. Here, we report for the first time that periodontal bacteria actively interplay with HPV-driven head and neck cancer stem cells (CSCs) via the activation of signaling pathways mediated by small extracellular vesicles (sEVs), leading to the rapid enrichment of CSCs during HPV-driven HNC progression and development. We observed an upregulation of Mediator Complex Subunit 27 (MED27) in sEVs derived from periodontal bacteria-infected HPV-driven HNC, as evidenced by 4D-microDIA quantitative proteomics analysis. Meanwhile, the silencing of MED27 resulted in the suppression of migratory, invasive, and sphere-forming abilities of HPV-driven HNC cells. Subsequent clinical data analysis revealed that the elevated level of MED27 was significantly correlated with aggressive clinicopathologic features and shorter survival in HNC patients. Most importantly, MED27 was expressed at a higher mRNA level in HPV-driven HNC patients when compared to controls and non-HPV-driven HNC patients, suggesting its potential as a diagnostic biomarker for HPV-driven HNC. This novel mechanistic insight could advance HPV-driven HNC diagnostic and therapeutic strategies.