Regulation of CD40 signaling in colon cancer cells and its implications in clinical tissues.

CD40 is a member of the tumor necrosis factor receptor family. We reveal here a correlation between CD40 expression and colon cancer differentiation. Upon CD40 ligand (CD40L) binding, CD40/CD40L signaling inhibited colon cancer proliferation, induced apoptosis, stalled cells at G0/G1, and influenced cell adhesion and metastasis. Clustering analysis identified the elevation of aryl hydrocarbon receptor repressor (AHRR) expression along with activation of CD40/CD40L signaling. Examination of clinical specimens revealed that both AHR and AHRR levels correlated with colon cancer histological grade. In addition, high expression of AHRR was associated with high expression of CD40 in tumor cells, with CD40L expression being particularly high in the tumor interstitium. Real-time PCR and western blotting analysis showed that AHRR expression in colon cancer cells was up-regulated by CD40L binding. The likely mediating signaling pathways for the effects of CD40 are described herein.