The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma.
Clear cell renal cell cancer (CC-RCC) is a highly chemoresistant tumor characterized by frequent inactivation of the von Hippel-Lindau (VHL) gene. The prognosis is reportedly worse in patients whose tumors express immunoreactive type I insulin-like growth factor receptor (IGF1R), a key mediator of tumor cell survival. We aimed to investigate how IGF1R expression is regulated, and found that IGF1R protein levels were unaffected by hypoxia, but were higher in CC-RCC cells harboring mutant inactive VHL than in isogenic cells expressing wild-type (WT) VHL. IGF1R mRNA and promoter activities were significantly lower in CC-RCC cells expressing WT VHL, consistent with a transcriptional effect. In Sp1-null Drosophila Schneider cells, IGF1R promoter activity was dependent on exogenous Sp1, and was suppressed by full-length VHL protein (pVHL) but only partially by truncated VHL lacking the Sp1-binding motif. pVHL also reduced the stability of IGF1R mRNA via sequestration of HuR protein. Finally, IGF1R mRNA levels were significantly higher in CC-RCC biopsies than benign kidney, confirming the clinical relevance of these findings. Thus, we have identified a new hypoxia-independent role for VHL in suppressing IGF1R transcription and mRNA stability. VHL inactivation leads to IGF1R upregulation, contributing to renal tumorigenesis and potentially also to chemoresistance.
Yuen
J S P
JS
Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, and Department of Urology, Churchill Hospital, Oxford, UK.
Cockman
M E
ME
Sullivan
M
M
Protheroe
A
A
Turner
G D H
GD
Roberts
I S
IS
Pugh
C W
CW
Werner
H
H
Macaulay
V M
VM
D002292:Carcinoma, Renal Cell / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000502:physiology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*
D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D017526:Receptor, IGF Type 1