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

脂质不仅是细胞膜的重要分子，而且在细胞间和细胞内通讯中也起信号分子的作用。它们在慢性炎症性肠病（IBD）和结肠癌中失调。鞘脂对于维持结肠上皮细胞中的膜屏障功能是重要的，但也对免疫细胞的迁移和细胞应激信号传导途径具有影响。它们是特定膜结构域“脂筏”的重要组成部分。脂筏还富含胆固醇和膜蛋白，其与细胞内蛋白接触以诱导信号传导途径。在我们的初步工作中，我们可以表明，特别是CerS4在人类结肠肿瘤中与对照组织相比显著下调。这在UICC I肿瘤中已经很明显，似乎是结肠癌发生的早期事件。我们想研究CerS4在结肠肿瘤中的表达是如何被调节的，以及CerS4的表达如何影响细胞信号转导通路，通过使用结肠癌细胞系以及来自人体组织的原代结肠上皮细胞，我们想分析影响CerS4表达的调节机制。研究了CerS4在转录水平上的表达调控和转录后调控机制。我们想弄清楚，CerS4表达如何影响体外和体内的癌变，增殖，迁移和集落形成。为此，将使用过表达或具有降低的CerS4表达的结肠上皮细胞。还应研究可能受CerS4表达影响的细胞信号传导途径。至少我们想知道CerS4是否适合作为结肠癌发生的标志物，是否应该被确定为肿瘤标志物，或者是否可以作为癌症治疗的新靶点。

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.