TCF/LEF function during intestinal maintenance and colon tumorigenesis

结直肠癌（CRC）是美国男性和女性中最常见的癌症之一，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大肠腺瘤性息肉病（APC）或b -连环蛋白的基因突变，这是Wnt信号通路的两个关键成分。在缺乏wnt的情况下，b -连环蛋白通常是GSK-3/Axin/APC复合物降解的靶标。在wnt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累，结合并激活Tcf/Lef蛋白。当Wnt信号不适当激活，b -连环蛋白在细胞核内积累时，就会出现息肉。

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.