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

CerS4在人结肠细胞中的调控及其在结肠癌发生中的作用

• 批准号: 428183001
• 负责人: Professorin Dr. Sabine Grösch
• 金额: --
• 依托单位: Institut für Klinische Pharmakologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428183001?language=en
• 关键词: Regulation; CerS4; un; human; colon

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.

脂质不仅是细胞膜的重要分子，而且还充当细胞间和细胞内通讯中的信号分子。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有影响。它们是特定膜域“脂筏”的重要组成部分。脂筏还富含胆固醇和膜蛋白，它们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，我们可以证明，与对照组织相比，CerS4 在人类结肠肿瘤中尤其显着下调。这在 UICC I 肿瘤中已经很明显，并且似乎是结肠癌发生的早期事件。我们想要研究CerS4表达在结肠肿瘤中是如何受到调节的，以及CerS4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体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。检查了 CerS4 表达在转录水平上的调节和转录后调节机制。我们想要阐明，CerS4 表达如何影响体外和体内的癌发生、增殖、迁移和集落形成。为此，将使用过度表达或降低 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，或者它是否可作为癌症治疗的新靶点。