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

脂类不仅是细胞膜的重要分子，而且在细胞间和细胞内的通讯中也起着信号分子的作用。在慢性炎症性肠病(IBD)和结肠癌中，它们都被解除了调控。鞘磷脂对维持结肠上皮细胞的膜屏障功能很重要，但也对免疫细胞的迁移和细胞应激信号通路产生影响。它们是特定膜结构域的重要组成部分，即“脂筏”。脂筏还富含胆固醇和膜蛋白，这些蛋白与细胞内蛋白接触，诱导信号通路。在我们的初步工作中，我们可能会发现，与对照组织相比，CerS4在人结肠肿瘤中的表达显著下调。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。我们想要研究CerS4在结肠肿瘤中的表达是如何调节的，以及CerS4的表达如何影响细胞信号通路。通过使用结肠癌细胞系以及来自人类组织的原代结肠上皮细胞，我们想要分析影响CerS4表达的调控机制。研究了CerS4在转录水平上的表达调控和转录后调控机制。我们想要阐明CerS4的表达如何在体外和体内影响肿瘤的发生、增殖、迁移和克隆形成。为此，将使用过表达或降低CerS4表达的结肠上皮细胞。此外，还应研究可能受CerS4表达影响的细胞信号通路。至少我们想知道CerS4是否适合作为结肠癌发生的标记物，是否应该被确定为肿瘤标记物，或者它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.