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

Abstract

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.

Keywords

CXCR4 / NF‐κB / head and neck cancer / invasion / signal transduction