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Cadherin-17 interacts with α2β1 integrin to regulate cell proliferation and adhesion in colorectal cancer cells causing liver metastasis

Abstract

Liver metastasis is the major cause of death associated to colorectal cancer. Cadherin-17 (CDH17) is a non-classical, seven domain, cadherin lacking the conserved cytoplasmic domain of classical cadherins. CDH17 was overexpressed in highly metastatic human KM12SM and present in many other colorectal cancer cells. Using tissue microarrays, we observed a significant association between high expression of CDH17 with liver metastasis and poor survival of the patients. On the basis of these findings, we decided to study cellular functions and signaling mechanisms mediated by CDH17 in cancer cells. In this report, loss-of-function experiments demonstrated that CDH17 caused a significant increase in KM12SM cell adhesion and proliferation. Coimmunoprecipitation experiments demonstrated an interaction between CDH17 and α2β1 integrin with a direct effect on β1 integrin activation and talin recruitment. The formation of this complex, together with other proteins, was confirmed by mass spectrometry analysis. CDH17 modulated integrin activation and signaling to induce specific focal adhesion kinase and Ras activation, which led to the activation of extracellular signal-regulated kinase and Jun N-terminal kinase and the increase in cyclin D1 and proliferation. In vivo experiments showed that CDH17 silencing in KM12 cells suppressed tumor growth and liver metastasis after subcutaneous or intrasplenic inoculation in nude mice. Collectively, our data reveal a new function for CDH17, which is to regulate α2β1 integrin signaling in cell adhesion and proliferation in colon cancer cells for liver metastasis.

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Acknowledgements

We thank Prof John M Luk (Hong Kong University) by the kind supply of CDH17 antibody. RA Bartolomé was supported by a grant to established research groups of the Asociación Española Contra el Cáncer (AECC). R Barderas was a recipient of a JAE-DOC/FSE Contract (CSIC) and is currently a fellow of the Ramón y Cajal program. S Torres was a recipient of a ProteoRed contract and Juan de la Cierva program. This research was supported by grant BIO2009-08818 from the Spanish Ministry of Science and Innovation, grant to established research groups (AECC) and grant S2010/BMD-2344/ Colomics2 from Comunidad de Madrid.

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Correspondence to J I Casal.

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Bartolomé, R., Barderas, R., Torres, S. et al. Cadherin-17 interacts with α2β1 integrin to regulate cell proliferation and adhesion in colorectal cancer cells causing liver metastasis. Oncogene 33, 1658–1669 (2014). https://doi.org/10.1038/onc.2013.117

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  • DOI: https://doi.org/10.1038/onc.2013.117

Keywords

  • Cadherin-17
  • α2β1 integrin
  • adhesion
  • proliferation
  • liver metastasis
  • colorectal cancer

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