TCF/LEF function during intestinal maintenance and colon tumorigenesis

结直肠癌（CRC）是美国男性和女性最常见的癌症之一，占新发癌症病例的约10%。结直肠癌是一种与年龄相关的上皮癌，通常需要二十多年才能从最初的良性腺瘤（息肉）进展为浸润性腺癌。大多数结肠癌的特征在于结肠腺瘤性息肉病（APC）或B-连环蛋白（Wnt信号通路的两个关键组分）中的基因突变。在不存在Wnt的情况下，B-连环蛋白通常被GSK-3/Axin/APC复合物靶向降解。在Wnt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累，并结合和反式激活Tcf/Lef蛋白。当Wnt信号不适当激活时，息肉就会出现，B-连环蛋白在细胞核中积累。 我们最近开发了一种新的结肠癌小鼠模型，其中小鼠产生的结肠肿瘤与人类FAP患者中发现的结肠肿瘤一致。作为该提议的一部分，我们将使用分子肿瘤水手进一步表征该模型。此外，使用小鼠遗传学，我们将通过功能获得和丧失研究严格测试Tcf 4在该小鼠结肠肿瘤模型中对结肠肿瘤形成的作用。Tcf 4是Tcf/Lef家族转录因子的成员，其对于小肠细胞增殖是必需的，并且在人结肠癌细胞系和原发性结肠肿瘤中表达。总之，这些研究的结果将为Tcf 4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Tcf 4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.