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The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma

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.

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Acknowledgements

We are grateful to P Waters for providing the S2 cells, David Cranston for samples of renal tumor and Danieli Generali for renal tumor cDNAs. We thank Alex Billioux, Anthony Yeh and Sylvia Barlett for technical assistance, and Adrian Harris and Ian Hickson for comments on the manuscript. JSY is sponsored by the Agency for Science, Technology and Research (A*STAR) and SingHealth, Singapore. This study was supported by Kidney Research UK Start-up grant RP5/2/2004 and by Cancer Research UK.

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Correspondence to V M Macaulay.

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Yuen, J., Cockman, M., Sullivan, M. et al. The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma. Oncogene 26, 6499–6508 (2007). https://doi.org/10.1038/sj.onc.1210474

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