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Updated: Aug 17, 2026

Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Concomitant deregulation of HIF1alpha and cell cycle proteins in VHL-mutated renal cell carcinomas
Derek John Atkins1, Christian Gingert, Christina Justenhoven
1Institute of Pathology, Helios-Kliniken Wuppertal, University Witten/Herdecke, Heusnerstrasse 40, 42283 Wuppertal, Germany. datkins@wuppertal.helios-kliniken.de
Abstract:
Renal cell carcinomas (RCCs) of the clear cell type are associated with alteration of the von Hippel-Lindau (VHL) tumour suppressor gene as well as subsequent stabilization and over-expression of hypoxia inducible factor (HIF), which causes up-regulation of cyclin D1. On the basis of their ability to interact with cyclin D1 we investigated a number of cell cycle proteins to shed further light on the downstream effects of HIF dysregulation. Expression of HIF1alpha, cyclin D1, cyclin-dependent kinase 4 and cyclin-dependent kinase inhibitors p16, p21 and p27 was studied by immunohistochemistry. Since NFkappaB1/RelA have been shown to bind to the cyclin D1 promoter, mRNA expression of these transcription factors was further analysed by quantitative PCR. In RCCs harbouring VHL mutations/hypermethylation, over-expression of HIF1alpha was parallelled by up-regulation of cyclin D1 and CDK4 and down-regulation of p21 and p27. Moreover, p27 expression was inversely correlated with tumour cell differentiation. Comparison of non-tumorous autologous kidney tissues revealed a significant down-regulation of NFkappaB1 mRNA expression in patients harbouring RCC with VHL mutations/hypermethylation. Our data support the notion of a link between VHL deficiency/HIF dysfunction and disturbances of cell cycle control in the tumorigenesis of VHL-negative RCC.
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