CXCL8 Drives MMP1 Upregulation and Promotes Metastatic Progression in Oral Cancer Through CXCR1/2-Mediated JAK1/STAT3 Activation.

BACKGROUND

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy, frequently diagnosed at advanced stages with regional and distant metastases that compromise survival. Identifying key molecular regulators of OSCC progression is essential for developing targeted therapies. Although CXCL8 is elevated in OSCC and linked to tumor progression, its precise pro-metastatic mechanisms and downstream effectors remain unclear.

METHODS

To identify key regulators of OSCC metastasis, we integrated bioinformatics analysis of multiple GEO datasets and identified CXCL8 as an upregulated hub gene in OSCC tissues. Functional assays were performed in OSCC cell lines (SCC4, SCC9, HSC3) to investigate the role of CXCL8 in cell migration and elucidate its downstream signaling pathways. An orthotopic tongue xenograft mouse model was established to validate the in vivo therapeutic relevance of targeting the CXCL8 pathway.

RESULTS

CXCL8 expression was significantly upregulated in OSCC tissues and strongly correlated with enhanced cell motility in OSCC cell lines. High CXCL8 expression was associated with poor overall survival in head and neck cancer patients. Mechanistically, CXCL8 upregulated matrix metalloproteinase 1 (MMP1) expression and enhanced cell migration through activation of the CXCR1/2-JAK1-STAT3 signaling axis. CXCL8 treatment induced JAK1 and STAT3 phosphorylation, promoted STAT3 nuclear translocation, and directly activated MMP1 promoter activity. Pharmacological inhibition or siRNA-mediated silencing of CXCR1/2, JAK1, STAT3, or MMP1 significantly reversed CXCL8-induced cell migration, wound healing, and MMP1 expression. In vivo, inhibition of CXCR1/2 reduced CXCL8 and MMP1 expression in primary tumors and cervical lymph nodes, limiting regional metastasis.

CONCLUSION

This study reveals that CXCL8 drives OSCC metastasis via CXCR1/2-mediated JAK1/STAT3 activation leading to MMP1 transcriptional upregulation. Our findings establish CXCL8 as both a prognostic biomarker and a promising therapeutic target, and suggest that targeting this pathway offers significant therapeutic potential for preventing OSCC metastatic progression.