细胞连接在肿瘤转移中具有重要作用。Ladinin 1(LAD1）位于半桥粒下方的基膜，在肿瘤中的作用及机制尚不清楚。我们发现LAD1在结直肠癌组织中表达显著下降或沉默，并与侵袭转移密切相关。转染LAD1抑制Wnt辅助受体LRP6的表达和结直肠癌细胞上皮-间质转化(EMT)。质谱和免疫共沉淀发现LAD1与TRIM21及p-LRP6相互结合。LRP6磷酸化招募Axin导致β-Catenin降解复合体解散。E3连接酶TRIM21参与蛋白泛素化降解。我们假设：LAD1募集TRIM21泛素化降解LRP6抑制WNT/β-Catenin通路，从而抑制结直肠癌发生EMT和转移。本项目将明确LAD1在结直肠癌转移中的作用，阐明LAD1对WNT通路的调节以及LAD1介导的LRP6降解是否依赖于TRIM21，从细胞连接蛋白促进WNT组件降解角度认识结直肠癌转移机制，为基于LAD1的结直肠癌诊疗提供理论依据。

Cell junctions play an important role in tumor metastasis. Ladinin 1 (LAD1) is located in the basal membrane beneath the hemidesmosomes and its role and mechanism in tumors is unclear. We found that LAD1 was significantly down-regulated or silenced in colorectal cancer and closely related to the invasion and metastasis. Overexpression of LAD1 inhibited Wnt co-receptor LRP6 expression and epithelial-mesenchymal transition (EMT). Mass spectrometry and co-immunoprecipitation revealed that LAD1 interacted with TRIM21 and LRP6. The recruitment of Axin by phosphorylated LRP6 results in the dissolution of the β-Catenin degradation complex. E3 ubiquitin ligase TRIM21 is involved in protein ubiquitination degradation. We hypothesized that LAD1 recruits TRIM21 to bind to LRP6 and inhibits the WNT/β-Catenin pathway by promoting LRP6 ubiquitination and degradation, thereby inhibiting EMT and metastasis of CRC. This project will first identify the role of LAD1 in CRC metastasis, and then clarify the regulation of LAD1 on the WNT pathway, and further explore whether LAD1-mediated degradation of LRP6 is dependent on TRIM21. This project understands the mechanism of CRC transfer from the perspective of cell junction protein promoting WNT component degradation, and provides a theoretical basis for the diagnosis and treatment of CRC based on LAD1.