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

Oncogene. 2007 Oct 4;26(45):6499-508. doi: 10.1038/sj.onc.1210474. Epub 2007 May 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Renal Cell / genetics*
  • Humans
  • Kidney / metabolism
  • Kidney Neoplasms / genetics*
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / metabolism*
  • Sp1 Transcription Factor / physiology
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • Up-Regulation*
  • Von Hippel-Lindau Tumor Suppressor Protein / physiology*


  • RNA, Messenger
  • Sp1 Transcription Factor
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Receptor, IGF Type 1