背景:Cadherin-17(CDH17),肠道细胞分化的标志,结合并激活α2β1整合素以促进结直肠癌(CRC)转移中的细胞粘附和增殖。此外,CDH17与p120-和β-联蛋白以尚未完全阐明的方式结合。在这份报告中,我们探索了参与这种关联的分子介质,它们对CRC传播的贡献和潜在的治疗影响。
方法:采用蛋白质组和共聚焦分析来鉴定和验证CDH17相互作用因子。功能表征涉及增殖的研究,迁移,和在代表各种表型的细胞系中的侵袭。在CRC组织微阵列(TMA)上进行免疫组织化学。进行体内动物实验用于转移研究。
结果:我们发现desmocollin-1(DSC1),桥粒钙粘蛋白,通过其细胞外结构域与CDH17相互作用。DSC1耗竭导致表现上皮或间充质表型的CRC细胞侵袭增加或减少,分别,在与p120-catenin相关的过程中。DSC1的下调导致上皮细胞中p120-连环蛋白同种型1的表达增加或间质细胞中细胞位置的改变。CDH17强制表达后观察到相反的结果。DSC1在肿瘤前缘的出芽细胞中高表达,并与干细胞样的不良预后有关,间充质CRC亚型,而在侵袭性较低的亚型中,与更有利的预后相关。体内实验表明,DSC1沉默降低肿瘤生长,肝脏归巢,和CRC间充质细胞的转移。此外,来自CDH17的合成肽,含有NLV基序,有效抑制体内侵袭和肝脏归巢,为开发针对桥粒钙粘蛋白的新疗法开辟了新的可能性。
结论:这些发现揭示了CDH17、DSC1和p120-catenin在CRC转移中的多方面作用,提供对针对低分化癌的桥粒钙黏着蛋白的潜在治疗干预措施的见解。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.