The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma
Yuen, J.S.P Cockman, M.E Sullivan, M Protheroe, A Turner, G.D.H Roberts, I.S Pugh, C.W Werner, H Macaulay, V.M
Cockman, M.E
Sullivan, M
Protheroe, A
Turner, G.D.H
Roberts, I.S
Pugh, C.W
Werner, H
Macaulay, V.M
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Alternative Title
Abstract
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. © 2007 Nature Publishing Group All rights reserved.
Keywords
HuR protein, somatomedin C receptor, transcription factor Sp1, von Hippel Lindau protein, animal cell, article, cell survival, clear cell carcinoma, controlled study, Drosophila, genetic transcription, human, human cell, hypoxia, kidney biopsy, kidney carcinoma, nonhuman, priority journal, prognosis, protein binding, protein expression, protein motif, protein stability, receptor upregulation, reverse transcription polymerase chain reaction, Carcinoma, Renal Cell, Humans, Kidney, Kidney Neoplasms, Receptor, IGF Type 1, RNA, Messenger, Sp1 Transcription Factor, Transcription, Genetic, Tumor Cells, Cultured, Up-Regulation, Von Hippel-Lindau Tumor Suppressor Protein
Source Title
Oncogene
Publisher
Series/Report No.
Collections
Rights
Attribution 4.0 International
Date
2007
DOI
10.1038/sj.onc.1210474
Type
Article