Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis

Cell Res. 2011 Apr;21(4):609-26. doi: 10.1038/cr.2011.17. Epub 2011 Feb 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / metabolism*
  • Cell Movement
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • Colorectal Neoplasms / metabolism*
  • Disease-Free Survival
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition
  • Gene Expression
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Liver Neoplasms / secondary
  • Lysosomes / metabolism
  • Mice
  • Mice, Nude
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Transplantation, Heterologous
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Cadherins
  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Receptors, Immunologic
  • roundabout protein
  • CBLL1 protein, human
  • Ubiquitin-Protein Ligases
  • Slit homolog 2 protein