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http://purl.uniprot.org/citations/26707870 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/26707870 | http://www.w3.org/2000/01/rdf-schema#comment | "BackgroundClear cell renal cell carcinomas (ccRCC) frequently display a loss of function of the von Hippel-Lindau (VHL) gene.ObjectiveTo elucidate the putative relationship between VHL mutation status and immune checkpoint ligand programmed death-ligand 1 (PD-L1) expression.Design, setting, and participantsA series of 32 renal tumors composed of 11 VHL tumor-associated and 21 sporadic RCCs were used to evaluate PD-L1 expression levels after sequencing of the three exons and exon-intron junctions of the VHL gene. The 786-O, A498, and RCC4 cell lines were used to investigate the mechanisms of PD-L1 regulation.Outcome measurements and statistical analysisFisher's exact test was used for VHL mutation and Kruskal-Wallis test for PD-L1 expression. If no covariate accounted for the association of VHL and PD-L1, then a Kruskal-Wallis test was used; otherwise Cochran-Mantel-Haenzsel test was used. We also used the Fligner-Policello test to compare two medians when the distributions had different dispersions.Results and limitationsWe demonstrated that tumors from ccRCC patients with VHL biallelic inactivation (ie, loss of function) display a significant increase in PD-L1 expression compared with ccRCC tumors carrying one VHL wild-type allele. Using the inducible VHL 786-O-derived cell lines with varying hypoxia-inducible factor-2 alpha (HIF-2α) stabilization levels, we showed that PD-L1 expression levels positively correlate with VHL mutation and HIF-2α expression. Targeting HIF-2α decreased PD-L1, while HIF-2α overexpression increased PD-L1 mRNA and protein levels in ccRCC cells. Interestingly, chromatin immunoprecipitation and luciferase assays revealed a direct binding of HIF-2α to a transcriptionally active hypoxia-response element in the human PD-L1 proximal promoter in 786-O cells.ConclusionsOur work provides the first evidence that VHL mutations positively correlate with PD-L1 expression in ccRCC and may influence the response to ccRCC anti-PD-L1/PD-1 immunotherapy.Patient summaryWe investigated the relationship between von Hippel-Lindau mutations and programmed death-ligand 1 expression. We demonstrated that von Hippel-Lindau mutation status significantly correlated with programmed death-ligand 1 expression in clear cell renal cell carcinomas."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.eururo.2015.11.029"xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Richard S."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Baud V."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Gad S."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Mami-Chouaib F."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Mejean A."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Rioux-Leclerc N."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Mole D.R."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Le Teuff G."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Escudier B."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Janji B."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Eggermont A.M."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Chouaib S."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Ferlicot S."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Hasmim M."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Messai Y."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Couve S."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Noman M.Z."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Albiges L."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/author | "Kammerer S.F."xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/date | "2016"xsd:gYear |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/name | "Eur Urol"xsd:string |
http://purl.uniprot.org/citations/26707870 | http://purl.uniprot.org/core/pages | "623-632"xsd:string |