Wnt/β-catenin/LEF1信号通路通过Rbp-jκ调节结肠癌发生发展的机制研究

研究表明Wnt/β-catenin/LEF1通路参与结肠癌发生发展，Notch通路异常激活是结肠癌诱发因素之一。我们前期研究发现：LEF1下调抑制结肠癌增殖、侵袭和转移，并调节Notch通路转录因子RBP-jκ表达，影响其启动子活性。提示Wnt通路与Notch通路在结肠癌发生发展中存在相互作用，但具体机制不明。本研究拟利用LEF1敲除小鼠及AOM诱导小鼠原位结肠癌模型等手段，全面分析Wnt/β-catenin/LEF1通路相关分子与RBP-jκ在结肠癌中表达的关系，探讨Wnt/β-catenin/LEF1通路调控RBP-jκ表达的机制及参与调节的下游分子。通过RBP-jκ对结肠癌细胞生物学行为影响的检测，试证实Wnt/β-catenin/LEF1通路通过其与Notch通路发生交互作用，共同参与结肠癌的发生发展过程，为深入理解结肠癌的发病机制，探寻结肠癌治疗的新靶点提供一定的理论依据。

Present studies showed that both Wnt/β-catenin/LEF1 and Notch has been involved in the carcinogenesis and development of colon cancer. Our group found the down-regulation of LEF1 could inhibit the growth, invasion and metastasis of colon cancer, regulate the expression of Notch pathway transcription factor RBP-jκ and inhibit its promoter activity. However, the cross-talk mechanisms between these two pathways have not been identified. In this project, we plan to analyse the difference of expression and interaction between Wnt/β-catenin/LEF1 pathway and RBP-jκ by LEF1 gene knock-out mice and AOM mouse model, deeply identify the model of Wnt/β-catenin/LEF1 in regulating RBP-jκ in colon cancer. At last, we aimed to clarify the cross-talk mechanism between Wnt/β-catenin/LEF1 pathway and Notch pathway through the impact of RBP-jκ on the colon cancer biology behavior. We want to comprehensively explain the molecular mechanisms of Wnt/β-catenin/LEF1 pathway in regulating RBP-jκ in colon cancer, which will provide a theoretical basis for the new molecules as therapeutic targets of colon cancer.