title: Regulation of E2F1 by the von Hippel-Lindau tumour suppressor protein predicts survival in renal cell cancer patients.
abstract: Biallelic mutations of the von Hippel-Lindau (VHL) gene are the most common cause of sporadic and inherited renal cell carcinoma (RCC). Loss of VHL has been reported to affect cell proliferation by deregulating cell cycle-associated proteins. We report that the VHL gene product (pVHL) inhibits E2F1 expression at both mRNA and protein level in zebrafish and human RCC cells, while loss of VHL increases E2F1 expression in patient kidney tumour tissue and RCC cells, resulting in a delay of cell cycle progression. RCCs from von Hippel-Lindau patients with known germline VHL mutations express significantly more E2F1 compared to sporadic RCCs with either clear-cell (cc) or non-cc histology. Analysis of 138 primary RCCs reveals that E2F1 expression is significantly higher in tumours with a diameter ≤7 cm and with a favourable American Joint Committee on Cancer (AJCC) stage. The expression of E2F1 in RCC significantly correlates with p27 expression, suggesting that increased expression of E2F1 in RCC induces tumour cell senescence via p27. Cox regression analysis shows significant prediction of E2F1 expression for disease-free survival and overall survival, implying that E2F1 expression in kidney tumour is a novel prognostic factor for patients with RCC.
authors.affiliation: Department of Medical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Dorus A
authors.initials: DA
authors.lastname: Mans
authors.forename: Joost S
authors.initials: JS
authors.lastname: Vermaat
authors.forename: Bart G
authors.initials: BG
authors.lastname: Weijts
authors.forename: Ellen
authors.initials: E
authors.lastname: van Rooijen
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Reeuwijk
authors.forename: Karsten
authors.initials: K
authors.lastname: Boldt
authors.forename: Laura G M
authors.initials: LG
authors.lastname: Daenen
authors.forename: Petra
authors.initials: P
authors.lastname: van der Groep
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Rowland
authors.forename: Judith J
authors.initials: JJ
authors.lastname: Jans
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Verhaar
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D016922:Cellular Senescence; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D030781:Organisms, Genetically Modified; D010957:Plasmids; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D014162:Transfection; D014407:Tumor Cells, Cultured; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*; D015027:Zebrafish
chemical_list: D050687:E2F1 Transcription Factor; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; D051794:Von Hippel-Lindau Tumor Suppressor Protein
keywords: E2F1; biomarker; hypoxia; renal cell carcinoma; von Hippel-Lindau (VHL)