Investigation of caspase-8 regulation and function in the development of colorectal cancer

Caspase-8在结直肠癌发生过程中的调控和功能研究

基本信息

批准号：
196244502
负责人：
Professor Dr. Christoph Becker
金额：
--
依托单位：
Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/196244502?language=en
关键词：
Investigation caspase regulation function development

项目摘要

Colorectal cancer is the most common cancer in the Western world. Intestinal epithelial cells play a crucial role in the development of colon cancer. Resistance to cell death is a a major driver of tumor development. Recently necroptosis was identified as a novel form of programmed necrosis. However its function in colorectal cancer has not yet been reported. Studies performed during the ongoing funding period demonstrate important functions of the necroptosis regulators RIP3 and caspase-8 in the homeostasis of the intestinal epithelium and suggest a role of this pathway in intestinal tumorigenesis. In fact, we have shown in preliminary studies that RIP3 has a tumor-promoting effect. In the present proposal we will take advantage of established mouse models for sporadic and inflammation-induced and metastatic colon cancer to study the functional role of necroptosis. In particular, we will elucidate and consolidated the necroptosis regulators RIP3 and caspase-8 in initiation, promotion and progression of colorectal cancer. Another objective of the proposal is to identify RIP3-dependent signaling pathways in dysplastic epithelial cells. Based on preliminary data, the influence of RIP3 on the WNT pathway will be intensively studied. In addition, tumor samples will be compared from RIP3 proficient and deficient mice for transcriptomic and proteomic differences. Finally, we will investigate whether modulation of necroptosis has an effect on the therapeutic (tumor cell killing) effect of established chemotherapeutic agents in the treatment of colorectal cancer such as 5-FU and innovative therapeutic approaches, such as SMAC mimetics. In summary, the proposal aims to characterize the role of necroptosis in colorectal cancer and will test whether modulation of necroptosis regulators has an effect on tumor development. The study will contribute to a broader understanding of cell death regulation in colorectal cancer and possibly to new innovative therapeutic approaches.

结直肠癌是西方世界上最常见的癌症。肠上皮细胞在结肠癌的发展中起着至关重要的作用。对细胞死亡的抗性是肿瘤发育的主要驱动力。最近，坏死性被确定为一种新型的编程坏死形式。然而，尚未报道其在结直肠癌中的功能。在正在进行的资金期间进行的研究表明，坏死性调节剂RIP3和caspase-8在肠上皮的稳态中的重要功能，并提出了该途径在肠道肿瘤发生中的作用。实际上，我们在初步研究中表明，RIP3具有肿瘤促进作用。在本提案中，我们将利用既定的小鼠模型用于散发性和炎症诱导的转移性结肠癌，以研究坏死性的功能作用。特别是，我们将在结直肠癌的起始，促进和进展中阐明和合并坏死调节剂RIP3和caspase-8。该提案的另一个目的是识别异增生性上皮细胞中RIP3依赖性信号通路。基于初步数据，将深入研究RIP3对WNT途径的影响。另外，将从RIP3熟练和缺乏转录组和蛋白质组学差异的小鼠中比较肿瘤样品。最后，我们将调查坏死性的调节是否对已建立的化学治疗剂在治疗结直肠癌的治疗（例如5-FU和创新的治疗方法，例如SMAC Mimetetics）中的治疗（肿瘤细胞杀死）作用。总而言之，该提案旨在表征坏死性在结直肠癌中的作用，并将测试坏死性调节剂的调节是否对肿瘤发育有影响。这项研究将有助于更广泛地了解结直肠癌的细胞死亡调节，并可能采用新的创新治疗方法。