Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Cell Res. 2011 Apr;21(4):609-26. doi: 10.1038/cr.2011.17. Epub 2011 Feb 1.
The Slit family of guidance cues binds to Roundabout (Robo) receptors and modulates cell migration. We report here that ectopic expression of Slit2 and Robo1 or recombinant Slit2 treatment of Robo1-expressing colorectal epithelial carcinoma cells recruited an ubiquitin ligase Hakai for E-cadherin (E-cad) ubiquitination and lysosomal degradation, epithelial-mesenchymal transition (EMT), and tumor growth and liver metastasis, which were rescued by knockdown of Hakai. In contrast, knockdown of endogenous Robo1 or specific blockade of Slit2 binding to Robo1 prevented E-cad degradation and reversed EMT, resulting in diminished tumor growth and liver metastasis. Ectopic expression of Robo1 also triggered a malignant transformation in Slit2-positive human embryonic kidney 293 cells. Importantly, the expression of Slit2 and Robo1 was significantly associated with an increased metastatic risk and poorer overall survival in colorectal carcinoma patients. We conclude that engagement of Robo1 by Slit2 induces malignant transformation through Hakai-mediated E-cad ubiquitination and lysosomal degradation during colorectal epithelial cell carcinogenesis.
Slit 家族的导向线索与 Roundabout（Robo）受体结合并调节细胞迁移。我们在这里报告，Slit2 和 Robo1 的异位表达或重组 Slit2 处理 Robo1 表达的结直肠上皮癌细胞招募了一种泛素连接酶 Hakai，用于 E-钙粘蛋白（E-cad）泛素化和溶酶体降解、上皮-间充质转化（EMT）以及肿瘤生长和肝转移，Hakai 的敲低可挽救这些过程。相比之下，内源性 Robo1 的敲低或 Slit2 与 Robo1 结合的特异性阻断可防止 E-cad 降解并逆转 EMT，从而导致肿瘤生长和肝转移减少。Robo1 的异位表达也触发了 Slit2 阳性的人胚肾 293 细胞的恶性转化。重要的是，Slit2 和 Robo1 的表达与结直肠癌患者转移风险增加和总体生存不良显著相关。我们得出结论，Slit2 与 Robo1 的结合通过 Hakai 介导的 E-cad 泛素化和溶酶体降解诱导结直肠上皮细胞癌变过程中的恶性转化。
