TCF/LEF function during intestinal maintenance and colon tumorigenesis

TCF/LEF 在肠道维持和结肠肿瘤发生过程中的功能

• 批准号: 8449513
• 负责人: MARIO R CAPECCHI
• 金额: $ 23.39万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449513
• 关键词: Adenocarcinoma; Adenomatous Polyposis Coli; Benign; Binding; Cell Nucleus; Cell Proliferation; Clinical; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Complex; Cytoplasm; Degradation Pathway; Drug Design; Epithelial; Family; Gene Mutation; Genetic; Glycogen Synthase Kinase 3; Human; Intestines; Maintenance; Malignant Neoplasms; Modeling; Molecular; Mus; Patients; Polyps; Proteins; Research; Role; Signal Pathway; Signal Transduction; Testing; Translational Research; United States; Woman; adenoma; age related; cancer therapy; colon cancer cell line; insight; loss of function; member; men; mouse model; novel; protein complex; transcription factor; tumor; tumorigenesis

Colorectal cancer (CRC) is one of the most common cancers in both men and women in the United States, and comprises about 10% of new cancer cases. Colorectal cancer is an age-related epithelial cancer that often takes over twenty years to progress from initial benign adenoma (polyp) to invasive adenocarcinoma. The majority of colon cancers are characterized by genetic mutations in adenomatous polyposis coli (APC) or B-catenin, two key components of the Wnt signaling pathway. In the absence of Wnts, B-catenin is normally targeted for degradation by the GSK-3/Axin/APC complex. In the presence of Wnts, this degradation pathway is inhibited, B-catenin accumulates in the cytoplasm and nucleus and binds and transactivates Tcf/Lef proteins. Polyps arise when there is inappropriate activation of Wnt signaling, and B-catenin protein accumulates in the nucleus. We have recently developed a new mouse model of colon cancer where mice develop colon tumors that are consistent with those found in human FAP patients. As part of this proposal, we will further characterize this model using molecular tumor mariners. Additionally using mouse genetics, we will rigorously test via gain and loss of function studies, the role of Tcf4 on colon tumor formation in this mouse colon tumor model. Tcf4 is a member of the Tcf/Lef family of transcription factors that is essential for small intestinal cell proliferation and is expressed in human colon cancer cell lines and primary colon tumors. Taken together, results from these studies will provide important new insights into the role of Tcf4 during colon tumor formation, and may reveal novel downstream targets of Tcf4 function.

结直肠癌 (CRC) 是美国男性和女性最常见的癌症之一，约占新发癌症病例的 10%。结直肠癌是一种与年龄相关的上皮癌，从最初的良性腺瘤（息肉）进展为侵袭性腺癌通常需要二十多年的时间。大多数结肠癌的特征是腺瘤性息肉病大肠杆菌 (APC) 或 B-连环蛋白（Wnt 信号通路的两个关键组成部分）的基因突变。在没有 Wnt 的情况下，B-连环蛋白通常是 GSK-3/Axin/APC 复合物降解的目标。当 Wnt 存在时，该降解途径被抑制，B-连环蛋白在细胞质和细胞核中积累，并结合并反式激活 Tcf/Lef 蛋白。当 Wnt 信号传导不当激活且 B-连环蛋白在细胞核中积聚时，就会出现息肉。 我们最近开发了一种新的结肠癌小鼠模型，小鼠会产生与人类 FAP 患者中发现的结肠肿瘤一致的结肠肿瘤。作为该提案的一部分，我们将使用分子肿瘤水手进一步表征该模型。此外，我们将使用小鼠遗传学，通过功能获得和丧失研究来严格测试 Tcf4 在该小鼠结肠肿瘤模型中对结肠肿瘤形成的作用。 Tcf4 是 Tcf/Lef 转录因子家族的成员，对小肠细胞增殖至关重要，在人结肠癌细胞系和原发性结肠肿瘤中表达。总而言之，这些研究的结果将为 Tcf4 在结肠肿瘤形成过程中的作用提供重要的新见解，并可能揭示 Tcf4 功能的新下游靶标。