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The role of TCF7L2 in colorectal tumorigenesis - oncogene or tumorsuppressor?

TCF7L2在结直肠肿瘤发生中的作用——癌基因还是抑癌基因？

基本信息

批准号：
315268620
负责人：
Professor Dr. Andreas Hecht
金额：
--
依托单位：
Institut für Molekulare Medizin und Zellforschung
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/315268620?language=en
关键词：
role TCF7L2 colorectal tumorigenesis oncogene

项目摘要

The transcription factor TCF7L2 (alias: TCF4) is a binding partner of beta-catenin and key nuclear effector of Wnt/beta-catenin signaling. TCF7L2 is essential for intestinal development and in adult tissue homeostasis. Paradoxically, up to 30% of human colorectal tumors carry mutations in the TCF7L2 gene. This makes TCF7L2 one of the most frequently mutated genes in colorectal cancer. Three different TCF7L2 mutational patterns are apparent: selective inactivation of a subset of TCF7L2 splice variants, 50% reduction of TCF7L2 expression by inactivation of one gene copy, and biallelic deletion. All three patterns lead to partial or complete loss of TCF7L2 function which is at odds with the absolute requirements for TCF7L2 in the healthy intestine and its role as driver of oncogene expression. Hence, the overall goal of the proposed studies is to clarify this apparent contradiction and to shed light on the pro- and anti-tumorigenic functions of TCF7L2 in colorectal cancer. Specifically we will test three hypotheses that could explain the occurrence of TCF7L2 mutational patterns and their impact on colorectal carcinogenesis. First, mutations that reduce the overall expression of TCF7L2 and particular TCF7L2 isoforms could provide a growth advantage to tumor cells by blocking the pro-differentiation function of Wnt/beta-catenin signaling while retaining its mitogenic activity. Second, the functional substitution of TCF7L2 by other TCF/LEF proteins which are pathologically upregulated in colorectal cancer cells, could allow the partial or complete inactivation of TCF7L2. Third, metastatic colorectal tumors might be able to tolerate complete TCF7L2 deletion because they might have acquired independence of beta-catenin/TCF7L2 driven transcription due to activation of Hedgehog/GLI signaling or overexpression of the intestinal stem cell transcription factor ASCL2. To test our hypotheses, we will use CRISPR/Cas9-mediated genome editing of colorectal cancer cells and intestinal organoid cultures from genetically modified mouse models to reconstruct the mutational patterns of TCF7L2 observed in human tumors. We will investigate how alterations of the TCF7L2 genotype affect tumor-relevant phenotypic traits, whether the TCF7L2 gene is essential in colorectal cancer cells, and whether upregulation of TCF/LEF family members, ASCL2 or Hedgehog/GLI activity can compensate for loss of TCF7L2. Bioinformatic analyses of publicly available transcriptome and genome data sets will be used as an independent strategy to interrogate relationships between TCF7L2 mutations, the expression of TCF/LEF family members, ASCL2, signature genes specifying Hedgehog/GLI activity, and as yet unknown features. Overall, the proposed studies will lead to novel insights into the biology of TCF7L2 and the molecular pathology of colorectal cancer. Thereby, they will provide the necessary basis for a rational evaluation of the beta-catenin::TCF7L2 complex as a suitable therapeutic target.

转录因子TCF7L2(别名：TCF4)是β-连环蛋白的结合伙伴，也是Wnt/β-连环蛋白信号转导的关键核效应因子。TCF7L2对肠道发育和成人组织动态平衡是必不可少的。矛盾的是，多达30%的人类大肠肿瘤携带TCF7L2基因突变。这使得TCF7L2成为结直肠癌中最常见的突变基因之一。有三种不同的TCF7L2突变模式：选择性失活TCF7L2剪接变异体的子集，通过失活一个基因拷贝使TCF7L2的表达减少50%，以及双等位基因缺失。所有这三种模式都会导致TCF7L2功能的部分或完全丧失，这与健康肠道对TCF7L2的绝对要求及其作为癌基因表达驱动因素的作用是不一致的。因此，拟议研究的总体目标是澄清这一明显的矛盾，并阐明TCF7L2在结直肠癌中的促肿瘤和抗肿瘤功能。具体地说，我们将测试三个假设，它们可以解释TCF7L2突变模式的发生及其对结直肠癌发生的影响。首先，降低TCF7L2和特定TCF7L2亚型整体表达的突变可以通过阻断Wnt/β-catenin信号的促分化功能而保持其有丝分裂活性，从而为肿瘤细胞提供生长优势。第二，TCF7L2的功能被其他在结直肠癌细胞中上调的TCF/Lef蛋白功能替代，可能允许TCF7L2部分或完全失活。第三，转移性大肠肿瘤可能能够耐受TCF7L2的完全缺失，因为它们可能由于Hedgehog/GLI信号的激活或肠道干细胞转录因子ASCL2的过表达而获得了β-连环蛋白/TCF7L2驱动的转录的独立性。为了验证我们的假设，我们将使用CRISPR/Cas9介导的结肠癌细胞和转基因小鼠模型中的肠道器官培养的基因组编辑来重建在人类肿瘤中观察到的TCF7L2的突变模式。我们将研究TCF7L2基因的改变如何影响肿瘤相关的表型特征，TCF7L2基因是否在结直肠癌细胞中是必需的，以及TCF/LEF家族成员、ASCL2或Hedgehog/GLI活性的上调是否可以弥补TCF7L2的丢失。对可公开获得的转录组和基因组数据集的生物信息学分析将被用作一种独立的策略，以询问TCF7L2突变、TCF/LEF家族成员、ASCL2、指定Hedgehog/GLI活性的签名基因以及未知特征之间的关系。总体而言，拟议的研究将为TCF7L2的生物学和结直肠癌的分子病理学带来新的见解。从而为合理评价β-连环蛋白：：TCF7L2复合体作为合适的治疗靶点提供了必要的基础。