title: Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations.
abstract: BACKGROUND
  Activation of the hypoxia-inducible transcription factors HIF-1 and HIF-2 and a HIF-independent defect in developmental apoptosis have been implicated in the pathogenesis of pheochromocytoma (PCC) associated with VHL, SDHB, and SDHD mutations.
  
  
  OBJECTIVE
  Our objective was to compare protein (HIF-1alpha, EPAS1, SDHB, JunB, CCND1, CD34, CLU) and gene (VEGF, BNIP3) expression patterns in VHL and SDHB/D associated tumors.
  
  
  RESULTS
  Overexpression of HIF-2 was relatively more common in VHL than SDHB/D PCC (12 of 13 vs. 14 of 20, P = 0.02), whereas nuclear HIF-1 staining was relatively more frequent in SDHB/D PCC (19 of 20 vs. 13 of 16, P = 0.04). In addition, CCND1 and VEGF expression (HIF-2 target genes) was significantly higher in VHL than in SDHB/D PCC. These findings suggest that VHL inactivation leads to preferential HIF-2 activation and CCND1 expression as described previously in VHL-defective renal cell carcinoma cell lines but not in other cell types. These similarities between the downstream consequences of VHL inactivation and HIF dysregulation in renal cell carcinoma and PCC may explain how inactivation of the ubiquitously expressed VHL protein results in susceptibility to specific tumor types. Both VHL and SDHB/D PCC demonstrated reduced CLU and SDHB expression. SDHB PCC are associated with a high risk of malignancy, and expression of (proapototic) BNIP3 was significantly lower in SDHB than VHL PCC.
  
  
  CONCLUSIONS
  Although inactivation of VHL and SDHB/D may disrupt similar HIF-dependent and HIF-independent signaling pathways, their effects on target gene expression are not identical, and this may explain the observed clinical differences in PCC and associated tumors seen with germline VHL and SDHB/D mutations.
authors.affiliation: Molecular and Populations Genetics laboratory, London Research Institute, Cancer Research UK, London, UK.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pollard
authors.forename: Mona
authors.initials: M
authors.lastname: El-Bahrawy
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: George
authors.initials: G
authors.lastname: Elia
authors.forename: Pip
authors.initials: P
authors.lastname: Killick
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelly
authors.forename: Toby
authors.initials: T
authors.lastname: Hunt
authors.forename: Rosemary
authors.initials: R
authors.lastname: Jeffery
authors.forename: Pooja
authors.initials: P
authors.lastname: Seedhar
authors.forename: Julian
authors.initials: J
authors.lastname: Barwell
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gleeson
authors.forename: Shirley V
authors.initials: SV
authors.lastname: Hodgson
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Stamp
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000378:metabolism*; D000313:Adrenal Medulla / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D010235:Paraganglioma / Q000235:genetics / Q000378:metabolism*; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013385:Succinate Dehydrogenase; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497446:VHL protein, human