Proteome profiling of clear cell renal cell carcinoma in von Hippel-Lindau patients highlights upregulation of Xaa-Pro aminopeptidase-1, an anti-proliferative and anti-migratory exoprotease

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• dc.contributor.author Drendel, Vanessa
• dc.contributor.author Heckelmann, Bianca
• dc.contributor.author Chen, Chia-yi
• dc.contributor.author Weisser, Juliane
• dc.contributor.author Espadas, Guadalupe
• dc.contributor.author Schell, Christoph
• dc.contributor.author Sabidó Aguadé, Eduard, 1981-
• dc.contributor.author Werner, Martin
• dc.contributor.author Jilg, Cordula A.
• dc.contributor.author Schilling, Oliver
• dc.date.accessioned 2023-12-18T06:54:39Z
• dc.date.available 2023-12-18T06:54:39Z
• dc.date.issued 2017
• dc.description.abstract Patients of the von Hippel-Lindau (VHL) disease frequently develop clear cell renal cell carcinoma (ccRCC). Using archived, formalin-fixed, paraffin-embedded (FFPE) samples, we sought to determine global proteome alterations that distinguish ccRCC tissue from adjacent, non-malignant kidney tissue in VHL-patients. Our quantitative proteomic analysis clearly discriminated tumor and non-malignant tissue. Significantly dysregulated proteins were distinguished using the linear models for microarray data algorithm. In the ccRCC tissue, we noticed a predominant under-representation of proteins involved in the tricarboxylic acid cycle and an increase in proteins involved in glycolysis. This profile possibly represents a proteomic fingerprint of the “Warburg effect”, which is a molecular hallmark of ccRCC. Furthermore, we observed an increase in proteins involved in extracellular matrix organization. We also noticed differential expression of many exoproteases in the ccRCC tissue. Of particular note were opposing alterations of Xaa-Pro Aminopeptidases-1 and -2 (XPNPEP-1 and -2): a strong decrease of XPNPEP-2 in ccRCC was accompanied by abundant presence of the related protease XPNPEP-1. In both cases, we corroborated the proteomic results by immunohistochemical analysis of ccRCC and adjacent, non-malignant kidney tissue of VHL patients. To functionally investigate the role of XPNPEP-1 in ccRCC, we performed small-hairpin RNA mediated XPNPEP-1 expression silencing in 786-O ccRCC cells harboring a mutated VHL gene. We found that XPNPEP-1 expression dampens cellular proliferation and migration. These results suggest that XPNPEP-1 is likely an anti-target in ccRCC. Methodologically, our work further validates the robustness of using FFPE material for quantitative proteomics.
• dc.description.sponsorship OS acknowledges support by Deutsche Forschungsgemeinschaft (SCHI 871/5, SCHI 871/8, SCHI 871/9, SCHI 871/11, INST 39/900-1 and SFB850-Project B8), and the Excellence Initiative of the German Federal and State Governments (EXC 294, BIOSS). This work has been supported by the PRIME-XS project, grant agreement number 262067, funded by the European Union 7th Framework Programme. The CRG/UPF Proteomics Unit is part of the “Plataforma de Recursos Biomoleculares y Bioinformáticos (ProteoRed)” supported by grant PT13/0001 of ISCIII and Spanish Ministry of Economy and Competitiveness. We acknowledge support of the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208, and from “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2014SGR678).
• dc.format.mimetype application/pdf
• dc.identifier.citation Drendel V, Heckelmann B, Chen C, Weisser J, Espadas G, Schell C, et al. Proteome profiling of clear cell renal cell carcinoma in von Hippel-Lindau patients highlights upregulation of Xaa-Pro aminopeptidase-1, an anti-proliferative and anti-migratory exoprotease. Oncotarget. 2017 Nov 19;8(59):100066-78. DOI: 10.18632/oncotarget.21929
• dc.identifier.doi http://dx.doi.org/10.18632/oncotarget.21929
• dc.identifier.issn 1949-2553
• dc.identifier.uri http://hdl.handle.net/10230/58551
• dc.language.iso eng
• dc.publisher Impact Journals
• dc.relation.ispartof Oncotarget. 2017 Nov 19;8(59):100066-78
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/262067
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SEV-2012-0208
• dc.rights Drendel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/3.0/
• dc.subject.keyword Von Hippel-Lindau disease;
• dc.subject.keyword Clear cell renal cell carcinoma
• dc.subject.keyword Formalin-fixation
• dc.subject.keyword Paraffin embedment
• dc.subject.keyword Proteomics
• dc.title Proteome profiling of clear cell renal cell carcinoma in von Hippel-Lindau patients highlights upregulation of Xaa-Pro aminopeptidase-1, an anti-proliferative and anti-migratory exoprotease
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion