Abstract
<title>Abstract</title> <p>Background Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with a high incidence of lymph node metastasis; however, the molecular mechanisms driving metastatic progression remain incompletely understood. Methods IL-8 expression profiles in OSCC were analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets and further validated in clinical specimens by RT-PCR. The functional role of IL-8 in metastatic progression was examined using Transwell migration assays and an orthotopic mouse model. NF-κB-mediated regulation of IL-8 transcription was evaluated using luciferase reporter assays. Results IL-8 expression was significantly elevated in OSCC tissues compared with normal tissues and was associated with unfavorable clinical outcomes. Ectopic expression of IL-8 in poorly metastatic Cal27 cells significantly enhanced migratory capacity, whereas IL-8 depletion in highly metastatic HSC3 cells reduced migration and lymph node metastatic dissemination in an orthotopic mouse model. Recombinant IL-8 restored the migratory ability of IL-8-deficient HSC3 cells, supporting a critical role of IL-8 in OSCC metastatic progression. Mechanistically, blockade of IL-8 signaling using the humanized anti-IL-8 antibody HuMax-IL8, the CXCR1/2 antagonist Reparixin, or NF-κB inhibitors significantly suppressed migration and NF-κB-dependent IL-8 transcription in OSCC cells. Furthermore, mutation of the NF-κB binding site within the IL-8 promoter abolished NF-κB-mediated transcriptional activation, demonstrating a functional IL-8/NF-κB positive feedback loop. Conclusions The IL-8/CXCR1/2/NF-κB signaling axis drives metastatic progression in OSCC and represents a potential prognostic biomarker and therapeutic target. Targeting this positive feedback loop may provide a promising strategy for patients with metastatic OSCC.</p>