CXCL12/SDF-1α Activates NF-κB and Promotes Oral Cancer Invasion through the Carma3/Bcl10/Malt1 Complex

Aim To determine how SDF-1 alpha/CXCR4 activates nuclear factor-kappa B (NF-kappa B) and promotes oral squamous cell carcinoma (OSCC) invasion. Methodology A lentivirus-based knockdown approach was utilized to deplete gene expression. NF-kappa B activation was evaluated by Western blot analysis and electrophoretic mobility shift (EMSA). Results We show that the activation of NF-kappa B by CXCR4 occurs through the Carma3/Bcl10/Malt1 (CBM) complex in OSCC. We found that loss of components of the CBM complex in HNSCC can inhibit SDF-1 alpha induced phosphorylation and degradation of I kappa B alpha, while TNF alpha induced IKK activation remains unchanged. Further, we identified a role for novel and atypical, but not classical, PKCs in activating IKK through CXCR4. Importantly, inhibition of the CBM complex leads to a significant decrease in SOP-la mediated invasion of OSCC. Conclusion The CBM complex plays a critical role in CXCR4-induced NF-kappa B activation in OSCC. Targeting molecular components of the NF-kappa B signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1 alpha.