Regulation of CerS4 un human colon cells and its role in colon carcinogenesis

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Lipids are not only important molecules of cellular membranes but function also as signalling molecules in the inter- and intra-cellular communication. They are deregulated in chronic inflammatory bowel disease (IBD) as well as in colon cancer. Sphingolipids are important for the maintenance of the membrane barrier function in colon epithelial cells but also have an influence on migration of immune cells and cellular stress signalling pathways. They are important components of specific membrane domains, the "lipid rafts". Lipid rafts are also enriched for cholesterol and membrane proteins which get in contact with intracellular proteins to induce signalling pathways. In our preliminary work we could show that especially CerS4 is significantly downregulated in human colon tumors in comparison to control tissue. This is already obvious in UICC I tumors and seems to be an early event in colon carcinogenesis. We want to investigate how CerS4 expression is regulated in colon tumors and how CerS4 expression can influence cellular signalling pathways.By the use of colon cancer cell lines as well as primary colon epithelial cells from human tissue we want to analyse the regulatory mechanisms influencing CerS4 expression. Regulation of CerS4 expression on transcriptional level and post-transcriptional regulatory mechanisms are examined. We want to clarify, how CerS4 expression influences carcinogenesis, proliferation, migration and colony formation in vitro and in vivo. For this, colon epithelial cells which either overexpress or have reduced CerS4 expression will be used. Also cellular signalling pathways should be investigated that may be influenced by CerS4 expression. At least we want to find out, if CerS4 is suitable as a marker for colon carcinogenesis and should be determined as tumormarker or if it is useful as a new target for cancer therapy.