The role of the EGFR in HIF-2-driven VHL(--) RCC tumorigenesis

Abstract

Inactivating mutations in the von Hippel-Lindau tumor suppressor gene are associated with renal cell carcinoma (VHL-/- RCC). The VHL protein targets the alpha subunits of hypoxia inducible factor (HIF) transcription factor for ubiquitination and degradation. VHL-/- RCC cells thus fail to degrade HIF-alpha, resulting in constitutive activation of HIF target genes and RCC tumorigenesis. Different HIF-alpha, isoforms exist, however, in RCC tumor formation is associated with HIF-2alpha. We previously demonstrated that HIF-dependent transforming growth factor alpha (TGF-alpha) production and subsequent epidermal growth factor receptor (EGFR) activation drives autonomous growth of VHL-loss RCC cells. Here we show that TGF-alpha is a HIF-2 specific target, and that the EGFR is required for HIF-2-dependent RCC tumor formation. RNA interference-mediated silencing of EGFR expression was sufficient to abrogate the growth autonomy, in vitro tumor spheroid formation, and in vivo tumorigenesis of VHL-/- RCC cells. These data identify EGFR as a critical determinant of HIF-2-dependent tumorigenesis and confirm EGFR as a central therapeutic target in VHL-loss kidney cancer.