Concomitant deregulation of HIF1alpha and cell cycle proteins in VHL-mutated renal cell carcinomas.
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.
Atkins
Derek John
DJ
Institute of Pathology, Helios-Kliniken Wuppertal, University Witten/Herdecke, Heusnerstrasse 40, 42283 Wuppertal, Germany. datkins@wuppertal.helios-kliniken.de
Gingert
Christian
C
Justenhoven
Christina
C
Schmahl
Gerd Emil
GE
Bonato
Marcellus Stephanus
MS
Brauch
Hiltrud
H
Störkel
Stephan
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human