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

• 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

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最常见的癌症。肠上皮细胞在结肠癌的发生发展中起着至关重要的作用。对细胞死亡的抵抗是肿瘤发展的主要驱动因素。最近发现坏死性上睑下垂是一种新型的程序性坏死。但其在结直肠癌中的作用尚未见报道。在持续资助期间进行的研究表明，坏死坏死调节因子RIP3和caspase-8在肠上皮稳态中的重要功能，并提示该途径在肠肿瘤发生中的作用。事实上，我们在前期研究中已经证明RIP3具有促肿瘤作用。在本研究中，我们将利用已建立的散发性、炎症性和转移性结肠癌小鼠模型来研究坏死下垂的功能作用。特别是，我们将阐明和巩固坏死下垂调控因子RIP3和caspase-8在结直肠癌的发生、促进和进展中的作用。该提案的另一个目的是鉴定发育不良上皮细胞中rip3依赖的信号通路。基于初步数据，RIP3对WNT通路的影响将被深入研究。此外，将比较RIP3熟练小鼠和RIP3缺乏小鼠的肿瘤样本的转录组学和蛋白质组学差异。最后，我们将研究坏死下垂的调节是否会影响结肠直肠癌治疗中现有化疗药物（如5-FU）和创新治疗方法（如SMAC模拟物）的治疗（肿瘤细胞杀伤）效果。总之，该提案旨在描述坏死性下垂在结直肠癌中的作用，并将测试坏死性下垂调节因子的调节是否对肿瘤发展有影响。这项研究将有助于更广泛地了解结直肠癌的细胞死亡调控，并可能带来新的创新治疗方法。