Regulation of Chemokine Receptor 7 expression by NF-κB in Squamous Cell Carcinoma of the Head and Neck (149.3)

Abstract

Abstract Aberrant expression of CCR7 has been detected in a number of human malignancies and been linked to pro-survival, invasive and metastatic pathways. In squamous cell carcinoma of the head and neck (SCCHN), we previously described the selective upregulation of CCR7 in metastatic tumors. However, the mechanism(s) of CCR7 expression have not been fully determined. In immune cells, inflammatory cytokines are known to upregulate CCR7 through NF-κB dependent mechanisms. Interestingly, NF-κB has been associated with CCR7 expression and an aggressive SCCHN phenotype. Thus, we hypothesized that NF-κB may be a key mediator of invasive and metastatic disease by promoting CCR7 expression in SCCHN tumors. Immunohistochemical staining of SCCHN tumors showed a strong positive correlation between NF-κB and CCR7 expression. Subsequently, we identified several NF-κB binding sites in the CCR7 promoter and investigated their activity using various assays. Our studies show that each κB motif displayed differential protein binding and transcriptional activation. The induction of NF-κB activity significantly increased CCR7 expression, while blocking NF-κB resulted in a corresponding decrease in CCR7 expression. Our findings support a role for NF-κB in the regulation of CCR7 expression in metastatic SCCHN. The observed NF-κB induction of CCR7 and its subsequent downstream pathways provide clinically important therapeutic targets to control the progression and metastasis of SCCHN tumors.