Ana Montero-Calle1, Maricruz Sánchez-Martínez1, Guillermo Solís-Fernández1,2, Alberto Peláez-García3, María Jesús Fernández-Aceñero4, Pilar Pallarés5, Miren Alonso-Navarro1, Marta Mendiola3, Jelle Hendrix6, David Hardisson3, Rubén A Bartolomé7, Johan Hofkens2,8, Susana Rocha9, Rodrigo Barderas10. 1. Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain. 2. Molecular Imaging and Photonics Division, Chemistry Department, Faculty of Sciences, KU Leuven, Celestijnenlaan 200F, 3001 Heverlee, Leuven, Belgium. 3. Molecular Pathology and Therapeutic Targets Group, La Paz University Hospital (IdiPAZ), E-28046, Madrid, Spain. 4. Surgical Pathology Department, Hospital Universitario Clínico San Carlos, E-28040, Madrid, Spain. 5. Unidades Centrales, Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain. 6. Dynamic Bioimaging Lab, Advanced Optical Microscopy Centre and Biomedical Research Institute, Hasselt University, Agoralaan C (BIOMED), 3590 Diepenbeek, Hasselt, Belgium. 7. Centro de Investigaciones Biológicas, CSIC, E-28040, Madrid, Spain. 8. Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany. 9. Molecular Imaging and Photonics Division, Chemistry Department, Faculty of Sciences, KU Leuven, Celestijnenlaan 200F, 3001 Heverlee, Leuven, Belgium. susana.rocha@kuleuven.be. 10. Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain. r.barderasm@isciii.es.
Abstract
BACKGROUND: Liver metastasis is the primary cause of colorectal cancer (CRC)-associated death. Aryl-hydrocarbon receptor-interacting protein (AIP), a putative positive intermediary in aryl-hydrocarbon receptor-mediated signalling, is overexpressed in highly metastatic human KM12SM CRC cells and other highly metastatic CRC cells. METHODS: Meta-analysis and immunohistochemistry were used to assess the relevance of AIP. Cellular functions and signalling mechanisms mediated by AIP were assessed by gain-of-function experiments and in vitro and in vivo experiments. RESULTS: A significant association of high AIP expression with poor CRC patients' survival was observed. Gain-of-function and quantitative proteomics experiments demonstrated that AIP increased tumorigenic and metastatic properties of isogenic KM12C (poorly metastatic) and KM12SM (highly metastatic to the liver) CRC cells. AIP overexpression dysregulated epithelial-to-mesenchymal (EMT) markers and induced several transcription factors and Cadherin-17 activation. The former induced the signalling activation of AKT, SRC and JNK kinases to increase adhesion, migration and invasion of CRC cells. In vivo, AIP expressing KM12 cells induced tumour growth and liver metastasis. Furthermore, KM12C (poorly metastatic) cells ectopically expressing AIP became metastatic to the liver. CONCLUSIONS: Our data reveal new roles for AIP in regulating proteins associated with cancer and metastasis to induce tumorigenic and metastatic properties in colon cancer cells driving liver metastasis.
BACKGROUND: Liver metastasis is the primary cause of colorectal cancer (CRC)-associated death. Aryl-hydrocarbon receptor-interacting protein (AIP), a putative positive intermediary in aryl-hydrocarbon receptor-mediated signalling, is overexpressed in highly metastatic human KM12SM CRC cells and other highly metastatic CRC cells. METHODS: Meta-analysis and immunohistochemistry were used to assess the relevance of AIP. Cellular functions and signalling mechanisms mediated by AIP were assessed by gain-of-function experiments and in vitro and in vivo experiments. RESULTS: A significant association of high AIP expression with poor CRC patients' survival was observed. Gain-of-function and quantitative proteomics experiments demonstrated that AIP increased tumorigenic and metastatic properties of isogenic KM12C (poorly metastatic) and KM12SM (highly metastatic to the liver) CRC cells. AIP overexpression dysregulated epithelial-to-mesenchymal (EMT) markers and induced several transcription factors and Cadherin-17 activation. The former induced the signalling activation of AKT, SRC and JNK kinases to increase adhesion, migration and invasion of CRC cells. In vivo, AIP expressing KM12 cells induced tumour growth and liver metastasis. Furthermore, KM12C (poorly metastatic) cells ectopically expressing AIP became metastatic to the liver. CONCLUSIONS: Our data reveal new roles for AIP in regulating proteins associated with cancer and metastasis to induce tumorigenic and metastatic properties in colon cancer cells driving liver metastasis.
Authors: Sofia Torres; Rubén A Bartolomé; Marta Mendes; Rodrigo Barderas; M Jesús Fernandez-Aceñero; Alberto Peláez-García; Cristina Peña; María Lopez-Lucendo; Roi Villar-Vázquez; Antonio García de Herreros; Felix Bonilla; J Ignacio Casal Journal: Clin Cancer Res Date: 2013-09-11 Impact factor: 12.531
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