Sphingosine-1-Phosphate Links Persistent STAT3 Activation, Chronic Intestinal Inflammation, and Development of Colitis-Associated Cancer

Inflammatory bowel disease is an important risk factor for colorectal cancer. We show that sphingosine-1-phosphate (SIP) produced by upregulation of sphingosine kinase 1 (SphK1) links chronic intestinal inflammation to colitis-associated cancer (CAC) and both are exacerbated by deletion of Sphk2. SIP is essential for production of the multifunctional NF-kappa B-regulated cytokine IL-6, persistent activation of the transcription factor STAT3, and consequent upregulation of the Si P receptor, 51PR1. The prodrug FTY720 decreased SphK1 and S1PR1 expression and eliminated the NF-kappa B/IL-6/STAT3 amplification cascade and development of CAC, even in Sphk2(-/-) mice, and may be useful in treating colon cancer in individuals with ulcerative colitis. Thus, the SphK1/S1P/S1PR1 axis is at the nexus between NF-kappa B and STAT3 and connects chronic inflammation and CAC.