PPARδ and PGE₂ signaling pathways communicate and connect inflammation to colorectal cancer

The nuclear hormone receptor peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-dependent transcription factor that is involved in fatty acid metabolism, obesity, wound healing, inflammation, and cancer. Despite decades of research, the role of PPARδ in inflammation and colorectal cancer remains unclear and somewhat controversial. Our recent work presented the first genetic evidence demonstrating that PPARδ is required for chronic colonic inflammation and colitis-associated carcinogenesis. We also found that a PPARδ downstream pathway, namely the COX-2-derived PGE₂ signaling, mediated crosstalk between tumor epithelial cells and macrophages to promote chronic inflammation and colitis-associated tumor genesis. In this brief review, we summarize recent studies on the role of PPARδ in inflammatory bowel disease (IBD) and colorectal cancer (CRC) and highlight recent advances in our understanding of how PPARδ and COX-2-drevided PGE₂ signaling coordinately promote chronic colonic inflammation and colitis-associate tumorigenesis. Elucidating the role of PPARδ in inflammation and CRC may provide a rationale for development of PPARδ antagonists as new therapeutic agents in treatment of IBD and CRC.