@article{f393527c171f49bab9e0f996e80b9ae5,
title = "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.",
keywords = "HuR, Renal cancer, Sp1, Type I IGF receptor, VHL",
author = "Yuen, {J. S.P.} and Cockman, {M. E.} and M. Sullivan and A. Protheroe and Turner, {G. D.H.} and Roberts, {I. S.} and Pugh, {C. W.} and H. Werner and Macaulay, {V. M.}",
year = "2007",
month = oct,
day = "4",
doi = "10.1038/sj.onc.1210474",
language = "אנגלית",
volume = "26",
pages = "6499--6508",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Springer Nature",
number = "45",
}