Down-regulation of sphingosine 1-phosphate receptor-1 in intestinal tumorigenesis

A17

Introduction: The bioactive sphingolipid, Sphingosine 1-Phosphate (S1P) is implicated in the regulation of cellular proliferation, migration, and survival via its G protein-coupled receptors S1P1-5. While animal models of intestinal neoplasia have demonstrated a beneficial effect of dietary sphingolipids in chemoprevention, the role of S1P in colon cancer is still unclear. The purpose of this study was to help define the role of the S1P receptor-ligand system in colon cancer.Methods: Small intestine specimens of bigenic S1P1+/-Apcmin and S1P1+/+Apcmin mice were compared to determine effect of S1P1 heterozygosity on polyp number. Growth inhibition of RIE-1 cells was assessed using enforced expression of S1P1 receptor by adenoviral vector followed by treatment with S1P. Matched human normal and cancer colon tissue were obtained from surgical specimens. Differential expression of S1P1 between the tissues was evaluated utilizing western blot analysis and immunohistochemistry.Results: Bigenic S1P1+/-Apcmin mice revealed a 27% increase in polyp number when compared to control mice. Induced expression of S1P1 in RIE-1 cells caused growth inhibition with treatment of S1P. Western blot analysis and immunohistochemistry revealed an increased expression of S1P1 in the human normal tissue as compared with tumor tissue.Conclusions: Our results suggest that S1P1 receptor functions in the intestinal epithelium to inhibit tumorigenesis. Down-regulation of S1P1 in colorectal cancer may have functional consequences in the proliferation and or metastatic spread of cancer. Further evaluation of Sphingosine 1-phosphate receptor-1 is necessary to determine its potential for therapeutic intervention in colon cancer.