title: 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.
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: R A
authors.initials: RA
authors.lastname: Bartolomé
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Barderas
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Torres
authors.affiliation: Pathology Department, Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Fernandez-Aceñero
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Mendes
authors.affiliation: Oncology Department, Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: García-Foncillas
authors.affiliation: Proteomics Core Facility, CIB-CSIC, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Lopez-Lucendo
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: J I
authors.initials: JI
authors.lastname: Casal
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D019073:HT29 Cells; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D014162:Transfection
chemical_list: C490584:CDH17 protein, human; D015820:Cadherins; D038982:Integrin alpha2beta1