Autocrine CCR7 signaling is mediated by NF‐kappaB in SCCHN

Abstract

The chemokine receptor CCR7 is a seven‐transmembrane G‐protein coupled receptor that is expressed by leukocytes and facilitates their chemotactic migration to the lymph nodes. However, aberrant CCR7 expression has been described in a number of human malignancies and is linked to metastatic behavior, pro‐survival, and invasive pathways. In squamous cell carcinoma of the head and neck (SCCHN), we have previously described the selective upregulation of CCR7 in metastatic, but not primary tumors. Strikingly, the metastatic SCCHN tumor cells also secrete and respond to the CCR7 ligands CCL19 and CCL21, suggesting that an autocrine signaling mechanism may promote self‐sufficiency of growth signals. Based on reports that the nuclear transcription factor NF‐kappaB regulates inflammatory genes involved in chemokine‐mediated tumorigenesis, we hypothesized that NF‐kappaB is a key mediator of autocrine CCR7 signaling in SCCHN. We identified four NF‐kappaB binding sites in the 900bp promoter region upstream of the CCR7 gene, and confirmed their activity using luciferase, EMSA and ChIP assays. Our findings argue that NF‐kappaB is important for the induction of CCR7 expression as well as for the propagation of downstream signaling pathways. The observed autocrine signaling and subsequent downstream NF‐kappaB activation appear to be important for the evolution and progression of metastatic SCCHN tumors.