Regulation of E2F1 by the von Hippel-Lindau tumour suppressor protein predicts survival in renal cell cancer patients

Dorus A. Mans, Joost S. Vermaat, Bart G. Weijts, Ellen Van Rooijen, Jeroen Van Reeuwijk, Karsten Boldt, Laura G M Daenen, Petra Van Der Groep, Benjamin D. Rowland, Judith J. Jans, Ronald Roepman, Emile E. Voest, Paul J. Van Diest, Marianne C. Verhaar, Alain De Bruin, Rachel H. Giles

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)117-129
Number of pages13
JournalJournal of Pathology
Volume231
Issue number1
DOIs
StatePublished - 2013
Externally publishedYes

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Von Hippel-Lindau Tumor Suppressor Protein
Renal Cell Carcinoma
Survival
Neoplasms
Kidney
Cell Cycle Proteins
Mutation
Cell Aging
Zebrafish
Genes
Disease-Free Survival
Histology
Cell Cycle
Regression Analysis
Cell Proliferation
Messenger RNA

Keywords

  • Biomarker
  • E2F1
  • Hypoxia
  • Renal cell carcinoma
  • Von Hippel-Lindau (VHL)

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Mans, D. A., Vermaat, J. S., Weijts, B. G., Van Rooijen, E., Van Reeuwijk, J., Boldt, K., ... Giles, R. H. (2013). Regulation of E2F1 by the von Hippel-Lindau tumour suppressor protein predicts survival in renal cell cancer patients. Journal of Pathology, 231(1), 117-129. https://doi.org/10.1002/path.4219

Regulation of E2F1 by the von Hippel-Lindau tumour suppressor protein predicts survival in renal cell cancer patients. / Mans, Dorus A.; Vermaat, Joost S.; Weijts, Bart G.; Van Rooijen, Ellen; Van Reeuwijk, Jeroen; Boldt, Karsten; Daenen, Laura G M; Van Der Groep, Petra; Rowland, Benjamin D.; Jans, Judith J.; Roepman, Ronald; Voest, Emile E.; Van Diest, Paul J.; Verhaar, Marianne C.; De Bruin, Alain; Giles, Rachel H.

In: Journal of Pathology, Vol. 231, No. 1, 2013, p. 117-129.

Research output: Contribution to journalArticle

Mans, DA, Vermaat, JS, Weijts, BG, Van Rooijen, E, Van Reeuwijk, J, Boldt, K, Daenen, LGM, Van Der Groep, P, Rowland, BD, Jans, JJ, Roepman, R, Voest, EE, Van Diest, PJ, Verhaar, MC, De Bruin, A & Giles, RH 2013, 'Regulation of E2F1 by the von Hippel-Lindau tumour suppressor protein predicts survival in renal cell cancer patients', Journal of Pathology, vol. 231, no. 1, pp. 117-129. https://doi.org/10.1002/path.4219
Mans, Dorus A. ; Vermaat, Joost S. ; Weijts, Bart G. ; Van Rooijen, Ellen ; Van Reeuwijk, Jeroen ; Boldt, Karsten ; Daenen, Laura G M ; Van Der Groep, Petra ; Rowland, Benjamin D. ; Jans, Judith J. ; Roepman, Ronald ; Voest, Emile E. ; Van Diest, Paul J. ; Verhaar, Marianne C. ; De Bruin, Alain ; Giles, Rachel H. / Regulation of E2F1 by the von Hippel-Lindau tumour suppressor protein predicts survival in renal cell cancer patients. In: Journal of Pathology. 2013 ; Vol. 231, No. 1. pp. 117-129.
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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.",
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AU - Daenen, Laura G M

AU - Van Der Groep, Petra

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AU - Voest, Emile E.

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