Wnt/β-catenin信号通路异常激活是导致结直肠癌发生的重要原因。我们近期研究初步发现LRP16在结直肠癌早期表达降低，抑制结直肠癌细胞中LRP16的表达可以促使β-catenin增多、促进TCF/LEF报告基因的活性，反之亦然。提示LRP16可能通过调控Wnt/β-catenin信号通路参与结直肠癌的发生过程。本项目拟开展以下研究：1）从分子水平阐明LRP16对Wnt信号通路的调控作用和分子机制；2）利用LRP16条件性敲除小鼠，从动物整体水平解析LRP16在结直肠癌发生中的作用；3）在临床组织标本水平，建立LRP16表达水平及分布与β-catenin定位、Wnt信号通路下游靶基因表达水平之间的相关性，揭示LRP16在结直肠癌发生中的临床意义；4）解析LRP16表达抑制的可能机制。本项目的完成将识别一条新的调控Wnt信号通路激活的分子路径，为结直肠癌的早期诊断和治疗提供新的选择。

Aberrant activation of the Wnt/β-catenin signaling is a major cause of colorectal cancer. Our recent study demonstrated that the expression of LRP16 was reduced in the early stage of colorectal carcinogenesis. Inhibition of LRP16 in human colorectal cancer cell lines increased β-catenin expression, TCF/LEF luciferase reporter activity; and vice versa. Based on these observations, the central hypothesis of the proposal is that LRP16 suppresses the tumorigenesis of colorectal cancer by inhibition of the Wnt/β-catenin signaling pathway. To test this hypothesis, we propose three objectives: 1) to determine how LRP16 suppresses Wnt/β-catenin signaling at molecular level. 2) To demonstrate the tumor suppressor effect of LRP16 in vivo by using tissue-specific LRP16 knockout mouse models. 3) To reveal the clinical significance of LRP16 in the tumorigenesis of colorectal cancer by investigating the relationship of LRP16 expression and its localization and the activation status of Wnt/?-catenin signaling. 4）To analyze the potential mechanism of inhibition of LRP16 expression in colorectal cancer. This project will identify a novel LRP16-mediated molecular pathway in regulating Wnt signaling; and will also provide a potential new therapeutic target for the early diagnosis and treatment of colorectal cancer.