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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.
Highlights
The von Hippel–Lindau gene product has a well-recognized role in the oxygen-dependent proteolysis of the a subunits of hypoxia-inducible factors 1 and 2 (HIF-1 and -2) (Maxwell et al, 1999). pVHL is the substrate recognition component of an E3 ubiquitin ligase complex that includes elongin C, elongin B, cullin 2 (Cul2) and Rbx1/ROC1 (VCB-CUL2; Cockman et al, 2000; Ohh et al, 2000; Conaway and Conaway, 2002)
Inactivating VHL mutations occur in approximately 75% of clear cell renal cell cancer (CC-RCC) (Gnarra et al, 1994), a highly vascular tumor which is characterized by extreme chemo- and radioresistance
IGF1R protein levels are higher in RCC cells lacking functional pVHL We began by assessing IGF1R expression in two human CC-RCC cell lines, RCC4/EV and 786-0/EV
Summary
The von Hippel–Lindau gene product (pVHL) has a well-recognized role in the oxygen-dependent proteolysis of the a subunits of hypoxia-inducible factors 1 and 2 (HIF-1 and -2) (Maxwell et al, 1999). pVHL is the substrate recognition component of an E3 ubiquitin ligase complex that includes elongin C, elongin B, cullin 2 (Cul2) and Rbx1/ROC1 (VCB-CUL2; Cockman et al, 2000; Ohh et al, 2000; Conaway and Conaway, 2002). The von Hippel–Lindau gene product (pVHL) has a well-recognized role in the oxygen-dependent proteolysis of the a subunits of hypoxia-inducible factors 1 and 2 (HIF-1 and -2) (Maxwell et al, 1999). The absence of oxygen-dependent hydroxylation of HIF-a prolines allows HIF-a subunits to accumulate, heterodimerize with HIF1b/ARNT and translocate to the nucleus, triggering transcription of hypoxia-inducible genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and carbonic anhydrase 9 (CA9; Semenza, 1999; Harris, 2002). Inactivating VHL mutations occur in approximately 75% of clear cell renal cell cancer (CC-RCC) (Gnarra et al, 1994), a highly vascular tumor which is characterized by extreme chemo- and radioresistance. Functional inactivation of pVHL allows normoxic accumulation of HIF-a subunits, leading to constitutive expression of hypoxia-inducible genes including those encoding angiogenic peptides. VHL mutation has been shown to be a critical factor in the pathogenesis of CC-RCC (Iliopoulos and Kaelin, 1997; Mandriota et al, 2002; Maranchie et al, 2002)
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