Regulation of E2F1 by the von Hippel-Lindau tumour suppressor protein predicts survival in renal cell cancer patients
- Authors
- Mans, D.A., Vermaat, J.S., Weijts, B.G., van Rooijen, E., van Reeuwijk, J., Boldt, K., Daenen, L.G., van der Groep, P., Rowland, B.D., Jans, J.J., Roepman, R., Voest, E.E., van Diest, P.J., Verhaar, M.C., de Bruin, A., and Giles, R.H.
- ID
- ZDB-PUB-130709-21
- Date
- 2013
- Source
- The Journal of pathology 231(1): 117-29 (Journal)
- Registered Authors
- van Rooijen, Ellen, Weijts, Bart
- Keywords
- Renal Cell Carcinoma, von Hippel-Lindau (VHL), biomarker, E2F1, hypoxia
- MeSH Terms
-
- Animals
- Blotting, Western
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/mortality*
- Carcinoma, Renal Cell/pathology
- Cellular Senescence
- Disease Models, Animal
- E2F1 Transcription Factor/genetics*
- E2F1 Transcription Factor/metabolism
- Female
- Gene Expression Regulation, Neoplastic/physiology*
- Humans
- Kidney Neoplasms/genetics
- Kidney Neoplasms/mortality*
- Kidney Neoplasms/pathology
- Male
- Middle Aged
- Organisms, Genetically Modified
- Plasmids
- Prognosis
- Proliferating Cell Nuclear Antigen/metabolism
- Proportional Hazards Models
- Real-Time Polymerase Chain Reaction
- Survival Rate
- Transfection
- Tumor Cells, Cultured
- Von Hippel-Lindau Tumor Suppressor Protein/physiology*
- Zebrafish
- PubMed
- 23744542 Full text @ J. Pathol.
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 d7 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.