title: VHL promotes immune response against renal cell carcinoma via NF-κB-dependent regulation of VCAM-1.
abstract: Vascular cell adhesion molecule 1 (VCAM-1) is an adhesion molecule assigned to the activated endothelium mediating immune cells adhesion and extravasation. However, its expression in renal carcinomas inversely correlates with tumor malignancy. Our experiments in clear cell renal cell carcinoma (ccRCC) cell lines demonstrated that von Hippel Lindau (VHL) loss, hypoxia, or PHD (for prolyl hydroxylase domain-containing proteins) inactivation decreased VCAM-1 levels through a transcriptional mechanism that was independent of the hypoxia-inducible factor and dependent on the nuclear factor κB signaling pathway. Conversely, VHL expression leads to high VCAM-1 levels in ccRCC, which in turn leads to better outcomes, possibly by favoring antitumor immunity through VCAM-1 interaction with the α4β1 integrin expressed in immune cells. Remarkably, in ccRCC human samples with VHL nonmissense mutations, we observed a negative correlation between VCAM-1 levels and ccRCC stage, microvascular invasion, and symptom presentation, pointing out the clinical value of VCAM-1 levels as a marker of ccRCC progression.
authors.affiliation: Department of Medicine, Instituto de Investigación Sanitaria Princesa, School of Medicine, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: David
authors.identifier: 0000-0001-9690-145X
authors.initials: D
authors.lastname: Labrousse-Arias
authors.affiliation: Department of Medicine, Instituto de Investigación Sanitaria Princesa, School of Medicine, Universidad Autónoma de Madrid, 28049 Madrid, Spain.|Research Departament, Instituto Ramón y Cajal de Investigación Sanitaria, 28034 Madrid, Spain.
authors.forename: Emma
authors.identifier: 0000-0001-6689-5335
authors.initials: E
authors.lastname: Martínez-Alonso
authors.affiliation: Department of Medicine, Instituto de Investigación Sanitaria Princesa, School of Medicine, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Corral-Escariz
authors.affiliation: Department of Medicine, Instituto de Investigación Sanitaria Princesa, School of Medicine, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Bienes-Martínez
authors.affiliation: Department of Medicine, Instituto de Investigación Sanitaria Princesa, School of Medicine, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Berridy
authors.affiliation: Molecular Oncology Lab, Centro Regional de Investigaciones Biomédicas, Biomedicine Unit, Universidad de Castilla la Mancha-Consejo Superior de Investigaciones Científicas, 02071 Albacete, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Serrano-Oviedo
authors.affiliation: Biomarckers and Therapeutic Targets, Instituto Ramón y Cajal de Investigación Sanitaria, 28034 Madrid, Spain.
authors.forename: Elisa
authors.identifier: 0000-0002-3751-9602
authors.initials: E
authors.lastname: Conde
authors.affiliation: Biomarckers and Therapeutic Targets, Instituto Ramón y Cajal de Investigación Sanitaria, 28034 Madrid, Spain.
authors.forename: María-Laura
authors.initials: ML
authors.lastname: García-Bermejo
authors.affiliation: Department of Urology, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain.
authors.forename: José M
authors.identifier: 0000-0003-3876-2919
authors.initials: JM
authors.lastname: Giménez-Bachs
authors.affiliation: Department of Urology, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain.
authors.forename: Antonio S
authors.identifier: 0000-0003-1837-6981
authors.initials: AS
authors.lastname: Salinas-Sánchez
authors.affiliation: Molecular Oncology Lab, Centro Regional de Investigaciones Biomédicas, Biomedicine Unit, Universidad de Castilla la Mancha-Consejo Superior de Investigaciones Científicas, 02071 Albacete, Spain.
authors.forename: Ricardo
authors.identifier: 0000-0003-0882-9780
authors.initials: R
authors.lastname: Sánchez-Prieto
authors.affiliation: Department of Urology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Biochemistry, Instituto de Investigaciones Biomédicas Alberto Sols, School of Medicine, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Marina
authors.identifier: 0000-0003-2245-3943
authors.initials: M
authors.lastname: Lasa
authors.affiliation: Department of Medicine, Instituto de Investigación Sanitaria Princesa, School of Medicine, Universidad Autónoma de Madrid, 28049 Madrid, Spain mariajose.calzada@uam.es.
authors.forename: María J
authors.identifier: 0000-0001-8615-960X
authors.initials: MJ
authors.lastname: Calzada
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000276:immunology*; D009154:Mutation / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000276:immunology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000276:immunology; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000276:immunology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039041:Integrin alpha4beta1; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D051794:Von Hippel-Lindau Tumor Suppressor Protein