VHL and HIF signalling in renal cell carcinogenesis

J Pathol. 2010 Jun;221(2):125-38. doi: 10.1002/path.2689.


Hypoxia-inducible factor (HIF) plays an important role in renal tumourigenesis. In the majority of clear cell RCC (ccRCC), the most frequent and highly vascularized RCC subtype, HIF is constitutively activated by inactivation of the von Hippel-Lindau gene. Of the HIF subunits, HIF-2alpha appears to be more oncogenic than HIF-1alpha, in that HIF-2alpha activates pro-tumourigenic target genes. In addition, recent studies indicate that HIF-1alpha, more than HIF-2alpha, can undergo proteasomal degradation in VHL - /- RCC cells. A more detailed understanding of the molecular basis of hypoxia and angiogenesis in renal carcinogenesis has set the stage for the development of targeted therapies, inhibiting multiple HIF-related pathways, such as the phosphatidylinositol 3-kinase-AKT-mTOR, RAS/RAF/MAP, and VEGF signalling routes. However, despite the positive results of these targeting agents in progression-free survival, clinical resistance remains an issue. Recent pre-clinical studies have suggested new targeting approaches such as inhibition of HIF-driven key metabolic enzymes and have introduced new HIF targeting agents, such as histone deacetylase inhibitors, with successful anti-neoplastic effects. In this review, we discuss existing and novel findings about RCC carcinogenesis, with subsequent clinical implications.

Publication types

  • Review

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carcinoma, Renal Cell / etiology*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / therapy
  • Cell Hypoxia / physiology
  • Fumarate Hydratase / genetics
  • Gene Silencing
  • Genes, Tumor Suppressor / physiology
  • Humans
  • Hypoxia-Inducible Factor 1 / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1 / genetics
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Kidney Neoplasms / etiology*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / therapy
  • Signal Transduction / genetics
  • Tocopherols
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
  • von Hippel-Lindau Disease / genetics
  • von Hippel-Lindau Disease / metabolism*


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • endothelial PAS domain-containing protein 1
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Fumarate Hydratase
  • VHL protein, human
  • Tocopherols