Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations.
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.
Pollard
Patrick J
PJ
Molecular and Populations Genetics laboratory, London Research Institute, Cancer Research UK, London, UK.
El-Bahrawy
Mona
M
Poulsom
Richard
R
Elia
George
G
Killick
Pip
P
Kelly
Gavin
G
Hunt
Toby
T
Jeffery
Rosemary
R
Seedhar
Pooja
P
Barwell
Julian
J
Latif
Farida
F
Gleeson
Michael J
MJ
Hodgson
Shirley V
SV
Stamp
Gordon W
GW
Tomlinson
Ian P M
IP
Maher
Eamonn R
ER
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
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