C-X-C motif chemokine ligand 13 and the C-X-C motif chemokine receptor 5-c-Jun N-terminal kinase-nuclear factor kappa B-matrix metalloproteinase 9 axis in oral squamous cell carcinoma metastasis.

BACKGROUND/PURPOSE: Metastasis is the leading cause of treatment failure in oral squamous cell carcinoma (OSCC). This study investigated the role of C-X-C motif chemokine ligand 13 (CXCL13) in OSCC metastasis and the underlying signaling mechanism.

MATERIALS AND

METHODS

Integrative transcriptomic analysis was performed using three independent OSCC datasets to identify metastasis-associated genes. CXCL13 expression was examined in OSCC tissues and highly migratory sublines. The effects of CXCL13 on cell migration were evaluated in vitro. Pathway analysis, pharmacological inhibitors, and receptor silencing were used to investigate the downstream signaling pathway. An orthotopic tongue xenograft model was used to evaluate the effect of CXCL13 knockdown on metastatic dissemination in vivo.

RESULTS

A total of 143 metastasis-associated genes were identified and were mainly enriched in extracellular matrix remodeling and invasion-related pathways. Among these genes, CXCL13 was identified as a central hub and was markedly upregulated in OSCC tissues and highly migratory sublines. CXCL13 significantly promoted OSCC cell migration. Mechanistically, CXCL13 activated C-X-C motif chemokine receptor 5 (CXCR5)-dependent c-Jun N-terminal kinase (JNK) signaling, which subsequently induced nuclear factor kappa B (NF-κB) activation and matrix metalloproteinase 9 (MMP9) expression. Pharmacological inhibition of JNK or NF-κB abolished CXCL13-induced migration. In vivo, CXCL13 knockdown significantly reduced metastatic dissemination without affecting primary tumor growth.

CONCLUSION

CXCL13 acts as a metastasis-associated regulator in OSCC and promotes tumor progression through the CXCL13-CXCR5-JNK-NF-κB-MMP9 axis. This signaling pathway may serve as a potential therapeutic target for limiting metastatic progression in OSCC.