This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Colorectal cancer is the second leading cause of cancer-related deaths in the US. In the previous work, we found that sphingosine kinase 1 (SK1)/sphingosine-1-phosphate (S1P) mediates cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) production in human colon cancer cells and colorectal cancer tissues excess SK1 protein and mRNA levels as compared to normal mucosa in an azoxymethane (AOM)-induced rodent model and human colon tumors using immunohistochemistry and real time RT-PCR. In this term, we extended these findings to investigate our hypothesis that the SK1/S1P pathway may play a pivotal role in colon carcinogenesis. We found that ethanol/dodecane delivery system penetrates S1P inside the cells and S1P regulates COX-2 promoter regions through S1P receptors and intracellular mechanism. SK1 overexpression enhanced cell growth, however, did not show colony formation on agarose and tumor growth in athymic mice. We found that SK1 deficiency significantly reduced AOM-induced aberrant crypt foci (ACF), preneoplastic lesions of colon cancers, in SK1 KO mice as compared to wild type mice. These results strongly support our hypothesis and SK1 may play a role in colon carcinogenesis. We are now ongoing the long term experiment of AOM-induced colon carcinogenesis using SK1 KO and wild type mice. In addition, we have already established tetracycline-on (tet-on) system in vitro to develop SK1 transgenic mice. In the next year, we will analyze colon cancer development in SK1 KO mice and SK1 transgenic mice, and establish role of the SK1/S1P pathway in colon carcinogenesis. We will investigate relationship between SK1/S1P and COX-2/PGE2 pathways to analyze the underlying mechanisms of this pathway in colon carcinogenesis.
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