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

AIM: To determine how SDF-1α/CXCR4 activates nuclear factor-kappa B (NF-κB) and promotes oral squamous cell carcinoma (OSCC) invasion. METHODOLOGY: A lentivirus-based knockdown approach was utilized to deplete gene expression. NF-κB activation was evaluated by Western blot analysis and electrophoretic mobility shift (EMSA). RESULTS: We show that the activation of NF-κB 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-1α induced phosphorylation and degradation of IκBα, while TNFα 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 SDF-1α mediated invasion of OSCC. CONCLUSION: The CBM complex plays a critical role in CXCR4-induced NF-κB activation in OSCC. Targeting molecular components of the NF-κB signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1α.