TCF/LEF function during intestinal maintenance and colon tumorigenesis

结直肠癌(CRC)是美国最常见的男性和女性癌症之一，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性癌症，通常需要20多年的时间才能从最初的良性腺瘤(息肉)发展为浸润性腺癌。大多数结肠癌的特征是结肠腺瘤性息肉病(APC)或B-连环蛋白(B-catenin)的基因突变，这是Wnt信号通路的两个关键组成部分。在没有WNTS的情况下，B-连环蛋白通常被GSK-3/Axin/APC复合体降解。在WNTS的存在下，这种降解途径被抑制，B-连环蛋白在细胞质和细胞核中积聚，并结合和反式激活Tcf/Lef蛋白。当Wnt信号被不适当地激活时，息肉就会发生，B-catenin蛋白在细胞核内积聚。 我们最近开发了一种新的结肠癌小鼠模型，其中小鼠患上结肠癌与在人类FAP患者中发现的肿瘤是一致的。作为这项提议的一部分，我们将使用分子肿瘤水手进一步描述这一模型。此外，利用小鼠遗传学，我们将通过功能获得和丧失研究，严格测试TCF4在这个小鼠结肠癌模型中对结肠癌形成的作用。TCF4是Tcf/Lef转录因子家族中的一员，对小肠细胞增殖至关重要，在人结肠癌细胞系和原发结肠癌中表达。综上所述，这些研究结果将为TCF4在结肠癌形成中的作用提供重要的新见解，并可能揭示TCF4功能的新下游靶点。

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.