The role of anti-apoptotic Bcl-2 proteins for colorectal cancer development and progression

抗凋亡 Bcl-2 蛋白在结直肠癌发生和进展中的作用

• 批准号: 227809315
• 负责人: Professor Dr. Henning Schulze-Bergkamen
• 金额: --
• 依托单位: Marien-Hospital Wesel
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/227809315?language=en
• 关键词: role; anti; apoptotic; Bcl; proteins

The Bcl (B-cell lymphoma)-2 protein family is mainly known due to its pivotal role in the regulation of the mitochondrial death pathway. Besides their inhibitory effects on mitochondrial activation, anti-apoptotic Bcl-2 proteins, such as Bcl-2, Bcl-xL and Mcl-1, also regulate cell cycle and proliferation. In colorectal cancer (CRC), changes in the expression levels of anti-apoptotic Bcl-2 proteins have been described. For example, increased expression of Bcl-xL in CRC tissue correlates with lower tumor differentiation and advanced disease stage. However, so far only little is known about the pathophysiological role of antiapoptotic Bcl-2 proteins in CRC progression. The focus of the subproject is to analyze the role of Bcl-2, Bcl-xL and Mcl-1 for the development, progression and metastases of CRC. First, we plan to investigate invasion, growth and metastases of human CRC cell lines in vitro and in vivo in a xenograft mouse model after manipulation of Mcl-1, Bcl-xL and Bcl-2 expression. Furthermore, we aim to analyze spontaneous as well as carcinogen-induced CRC development and progression in intestinal-specific Mcl-1, Bcl-xL and Bcl-2 knockout mouse models. In addition, we intend to investigate expression patterns of Mcl-1, Bcl-xL and Bcl-2 and their prognostic value in human CRC samples including circulating and disseminated tumor cells. Primary tumors as well as corresponding lymph node and liver metastases will be analysed by high-resolution automated microscopy to map Bcl-2 protein expression in tumor samples. Finally, miRNA profiling in sera and tissue samples of CRC patients should help to identify miRNAs relevant for the regulation of Bcl-2, Bcl-xL and Mcl-1. In conclusion, our project intends to specify the role of anti-apoptotic Bcl-2 proteins in the development and progression of CRC. This may help to identify individual treatment approaches in the near future, since strategies for inhibition of anti-apoptotic Bcl-2 proteins have already entered late-phase clinical trials.

Bcl（B细胞淋巴瘤）-2蛋白家族主要是由于其在线粒体死亡途径的调节中的关键作用而已知的。除了对线粒体活化的抑制作用外，抗凋亡Bcl-2蛋白，如Bcl-2、Bcl-xL和Mcl-1，也调节细胞周期和增殖。在结直肠癌（CRC）中，已经描述了抗凋亡Bcl-2蛋白的表达水平的变化。例如，CRC组织中Bcl-xL的表达增加与较低的肿瘤分化和晚期疾病阶段相关。然而，到目前为止，关于抗凋亡Bcl-2蛋白在CRC进展中的病理生理作用知之甚少。该子项目的重点是分析Bcl-2、Bcl-xL和Mcl-1在结直肠癌发生、发展和转移中的作用。首先，我们计划在异种移植小鼠模型中研究在操纵Mcl-1、Bcl-xL和Bcl-2表达后人CRC细胞系在体外和体内的侵袭、生长和转移。此外，我们的目的是分析自发的以及致癌物诱导的CRC的发展和进展，在特定的Mcl-1，Bcl-xL和Bcl-2基因敲除小鼠模型。此外，我们打算研究Mcl-1，Bcl-xL和Bcl-2的表达模式及其在人类CRC样本（包括循环和播散的肿瘤细胞）中的预后价值。原发性肿瘤以及相应的淋巴结和肝转移将通过高分辨率自动显微镜进行分析，以绘制肿瘤样品中的Bcl-2蛋白表达。最后，CRC患者血清和组织样本中的miRNA谱分析应该有助于鉴定与Bcl-2、Bcl-xL和Mcl-1的调节相关的miRNA。总之，我们的项目旨在明确抗凋亡Bcl-2蛋白在CRC发生和进展中的作用。这可能有助于在不久的将来确定个体治疗方法，因为抑制抗凋亡Bcl-2蛋白的策略已经进入后期临床试验。