Department of Biomolecular Medicine, Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, Madrid, 28040, Spain.
Biochemistry Department, Universidad Autónoma de Madrid, Madrid, Spain.
J Exp Clin Cancer Res. 2024 Jan 24;43(1):31. doi: 10.1186/s13046-024-02956-6.
Cadherin-17 (CDH17), a marker of differentiation in intestinal cells, binds and activates α2β1 integrin to promote cell adhesion and proliferation in colorectal cancer (CRC) metastasis. Furthermore, CDH17 associates with p120- and β-catenin in a manner yet to be fully elucidated. In this report, we explored the molecular mediators involved in this association, their contribution to CRC dissemination and potential therapeutic implications.
Proteomic and confocal analyses were employed to identify and validate CDH17 interactors. Functional characterization involved the study of proliferation, migration, and invasion in cell lines representative of various phenotypes. Immunohistochemistry was conducted on CRC tissue microarrays (TMA). In vivo animal experiments were carried out for metastatic studies.
We found that desmocollin-1 (DSC1), a desmosomal cadherin, interacts with CDH17 via its extracellular domain. DSC1 depletion led to increased or decreased invasion in CRC cells displaying epithelial or mesenchymal phenotype, respectively, in a process mediated by the association with p120-catenin. Down-regulation of DSC1 resulted in an increased expression of p120-catenin isoform 1 in epithelial cells or a shift in cellular location in mesenchymal cells. Opposite results were observed after forced expression of CDH17. DSC1 is highly expressed in budding cells at the leading edge of the tumor and associates with poor prognosis in the stem-like, mesenchymal CRC subtypes, while correlates with a more favorable prognosis in the less-aggressive subtypes. In vivo experiments demonstrated that DSC1 silencing reduced tumor growth, liver homing, and metastasis in CRC mesenchymal cells. Furthermore, a synthetic peptide derived from CDH17, containing the NLV motif, effectively inhibited invasion and liver homing in vivo, opening up new possibilities for the development of novel therapies focused on desmosomal cadherins.
These findings shed light on the multifaceted roles of CDH17, DSC1, and p120-catenin in CRC metastasis, offering insights into potential therapeutic interventions for targeting desmosomal cadherins in poorly-differentiated carcinomas.
钙黏蛋白 17（CDH17）是一种肠道细胞分化标志物，它可以结合并激活α2β1 整联蛋白，从而促进结直肠癌（CRC）转移中的细胞黏附和增殖。此外，CDH17 与 p120 和β-catenin 以尚未完全阐明的方式相关联。在本报告中，我们探索了涉及这种关联的分子介质，它们对 CRC 传播的贡献以及潜在的治疗意义。
采用蛋白质组学和共聚焦分析来鉴定和验证 CDH17 的相互作用子。功能表征涉及对各种表型代表的细胞系进行增殖、迁移和侵袭研究。对 CRC 组织微阵列（TMA）进行免疫组织化学分析。进行体内动物实验以进行转移研究。
我们发现桥粒钙黏蛋白 1（DSC1），一种桥粒钙黏蛋白，通过其细胞外结构域与 CDH17 相互作用。DSC1 耗竭导致具有上皮或间质表型的 CRC 细胞的侵袭增加或减少，这一过程是通过与 p120-catenin 相关联介导的。上皮细胞中 p120-catenin 同工型 1的表达增加或间质细胞中细胞位置的改变，是 DSC1 下调的结果。CDH17 过表达则观察到相反的结果。DSC1 在肿瘤前沿的芽生细胞中高度表达，与 CRC 间质亚型的不良预后相关，而与侵袭性较低的亚型相关联则与较好的预后相关。体内实验表明，DSC1 沉默减少了 CRC 间质细胞的肿瘤生长、肝归巢和转移。此外，一种源自 CDH17 的包含 NLV 基序的合成肽，在体内有效地抑制了侵袭和肝归巢，为开发针对桥粒钙黏蛋白的新型治疗方法开辟了新的可能性。
这些发现揭示了 CDH17、DSC1 和 p120-catenin 在 CRC 转移中的多方面作用，为针对低分化癌中的桥粒钙黏蛋白的潜在治疗干预提供了见解。
