Cancer-associated fibroblast-derived interleukin-6 as a key driver of epithelial-mesenchymal transition and metastasis in oral squamous cell carcinoma.

BACKGROUND/PURPOSE: Oral squamous cell carcinoma (OSCC) is a highly metastatic cancer with a poor prognosis, partly driven by epithelial-mesenchymal transition (EMT). Although several cytokines have been implicated in OSCC progression, the specific role of cancer-associated fibroblast (CAF)-derived interleukin-6 (IL-6) in EMT and metastasis remains poorly understood. This study investigated the contribution of CAF-derived IL-6 to the promotion of EMT and metastasis in OSCC. MATERIALS AND METHODS: Conditioned media from gingival fibroblasts (GF) treated with OSCC-conditioned media (SCC25-GF CM) were analyzed using secretomic and functional assays. EMT marker expression, migration, and invasion were evaluated by RT-qPCR, Western blotting, immunofluorescence, and an IL-6 neutralizing antibody. RESULTS: SCC25-GF CM significantly downregulated E-cadherin and upregulated N-cadherin, vimentin, and Snail expression, indicating EMT induction. Secretome analysis revealed elevated levels of multiple EMT- and metastasis-associated factors, including stromelysin-1, glia-derived nexin, tenascin, procathepsin L, and IL-6, in SCC25-GF CM. IL-6 neutralization reduced EMT marker expression, migration, and invasion in SCC25 cells, demonstrating that IL-6 is a key driver of CAF-mediated EMT in OSCC. CONCLUSION: These findings indicate that IL-6 is a central mediator of CAF-induced EMT and contributes to the metastatic potential of OSCC, highlighting IL-6 as a promising therapeutic target.