复发转移是影响结直肠癌预后的重要原因之一，亟需寻找新肠癌相关分子标记物指导临床诊治。申请者前期研究发现CSN6在复发结直肠癌中高表达并能被ERK磷酸化，是结直肠癌新型分子标记物（Cancer Cell，2015）。然而CSN6下游的调控机制尚不明确。我们前期预实验发现CSN6能结合并降低TRIM21表达，由此提出“CSN6调控TRIM21影响肠癌”的假设。本项目将首先通过提高或沉默TRIM21的表达探索其在结直肠癌中的作用，然后结合3D结构预测、多种分子及蛋白实验明确CSN6对TRIM21的调控机制，接着研究TRIM21对下游潜在通路的作用及其对结直肠癌的影响，最后利用小鼠模型和临床样本验证CSN6-TRIM21通路的表达及与结直肠癌复发转移的相关性。本研究将从“细胞-动物-临床”多层次阐明CSN6通过调节TRIM21在结直肠癌复发转移中的作用及机制，为结直肠癌靶向治疗提供新的思路。

Identifying new prognostic biomarkers that can predict outcome of colorectal cancer could contribute significantly to the treatment in CRC patients. We found that CSN6 was phosphorylated by ERK and correlated with poorer colorectal cancer patient survival. CSN6 is a novel biomarker for colorectal cancer (Cancer Cell, 2015). But the detail mechanism of CSN6 downstream is still unclear. We found that CSN6 can bind to and regulate TRIM21 expression, Therefore, we propose a hypothesis that“CSN6 regulate TRIM21 and colorectal cancer”. In this study, we will explore the function of TRIM21 in CRC by protein overexpression or RNAi-mediated downregulation assays; 3D prediction, COIP and point mutation was used to find the binding site of CSN6 and TRIM21. Ubiquitination assay and protein cycle assay to investigate the mechanism of regulation of TRIM21 by CSN6. By using in vivo and in vitro experiments, we could study the role of CSN6 in CRC from multi-levels. Our study will provide basic knowledge for future therapy of the CSN6-TRIM21 signaling pathway.