Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation

Background and Aims Colitis-associated cancer (CAC) is one of the most serious complications in patients with inflammatory bowel disease. Sphingosine kinase 1 (Sphk1) is a key enzyme in the sphingolipid pathway and has oncogene potential for inducing both initiation and progression of tumors. The aim of this work is to characterize the role of epithelial Sphk1 in mouse colitis and CAC models. Methods We investigated the roles of Sphk1 in CAC by conditional deletion of Sphk1 in intestinal epithelial cells (IECs). Results CAC was induced in both Sphk1 ΔIEC /Apc Min/+ and Sphk1 IEC /Apc Min/+ mice by administration of 2% dextran sodium sulfate (DSS) for 7 days. Genetic deletion of Sphk1 significantly reduced the number and size of tumors in Apc Min/+ mice. Histologic grade was more severe in Sphk1 ΔIEC /Apc Min/+ mice compared with Sphk1 IEC /Apc Min/+ mice (invasive carcinoma, 71% versus 13%, p