The molecular mechanism of human beta-defensin 1 in inhibiting the progression of head and neck squamous cell carcinoma: The role of the IL-17B/IL-17RB/TRAF6/NF-κB signaling axis.

The present study aimed to investigate the regulatory functions and mechanisms of human β-defensin 1 (hBD-1) in head and neck squamous cell carcinoma (HNSCC) through comprehensive bioinformatics analyses and experimental validation. Comprehensive bioinformatics analyses of TCGA database samples were performed, including DEFB1 expression profiling, clinical correlation analysis, prognostic evaluation, and pathway enrichment studies. The results demonstrated that DEFB1/hBD-1 expression was significantly downregulated in tumor tissues and negatively correlated with key genes in the IL-17 signaling pathway, while being associated with reduced lymph node metastasis and improved overall survival. Immunohistochemical validation confirmed low hBD-1 protein expression in HNSCC tissues. Assessment of hBD-1 expression across multiple HNSCC cell lines revealed consistently downregulated hBD-1 mRNA and protein levels. Functional experiments using stable hBD-1-overexpressing cell models demonstrated that hBD-1 overexpression significantly inhibited cell metabolic activity, clone formation, invasion, and migration while effectively inducing apoptosis. Mechanistic studies revealed that hBD-1 suppressed the IL-17B/IL-17RB/TRAF6/NF-κB signaling pathway by downregulating IL-17B and IL-17RB expression, inhibiting TRAF6 ubiquitination, and decreasing NF-κB pathway protein phosphorylation levels. In vivo xenograft experiments validated that hBD-1 overexpression significantly reduced tumor growth, volume, cell proliferation, and increased apoptosis. These findings collectively demonstrate that DEFB1/hBD-1 functions as a tumor suppressor in HNSCC through suppression of the IL-17B/IL-17RB/TRAF6/NF-κB axis, positioning it as a potential prognostic biomarker and therapeutic target for HNSCC management.