Expression of hypoxia inducible factor-1alpha and 2alpha in genetically distinct early renal cortical tumors.
OBJECTIVE
The role of the HIF class of transcription factors has been implicated to be a critical step in clear cell kidney tumorigenesis. To assess if HIF over expression is a prominent feature of other renal cell carcinoma histological subtypes we characterized the expression of HIF-1alpha and HIF-2alpha in genetically distinct early renal cortical tumors.


METHODS
Nascent renal tumors of distinct histology from patients with a hereditary renal tumor syndrome were characterized for HIF expression using high amplification immunohistochemistry. In addition, indirect immunofluorescence and confocal microscopy were used for subcellular localization of HIF-1alpha and 2alpha in clear cell renal carcinoma cells.


RESULTS
Clear cell RCC tumors from patients with von Hippel-Lindau disease strongly expressed HIF-1alpha and HIF-2alpha (10 of 12 and 12 of 12 tumors, respectively). Chromophobe tumors from patients with Birt-Hogg-Dubé syndrome expressed predominantly HIF-2alpha with weaker HIF-1alpha expression (12 of 12 and 6 of 12 tumors, respectively). Consistent HIF-1alpha expression was not seen in type I papillary tumors from patients with hereditary papillary renal carcinoma (3 of 12 tumors). However, half of the type I papillary tumors (6 of 12) expressed HIF-2alpha.


CONCLUSIONS
Differential patterns of HIF-1alpha and HIF-2alpha protein over expression were found among the 3 human kidney tumor types associated with multifocal hereditary kidney tumor syndromes. Consistent, simultaneous over expression of HIF-1alpha and HIF-2alpha appears to be specific to VHL negative clear cell renal cell carcinoma. Consistent HIF-2alpha expression was found in all 3 renal cortical tumor subtypes, suggesting a pivotal role in renal cortical tumorigenesis. Differential function of HIF-1alpha vs HIF-2alpha is suggested by the distinct subcellular localization pattern of HIF-1alpha and HIF-2alpha in clear cell renal carcinoma cells.
Kim
Chong M
CM
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1107, USA.
Vocke
Cathy
C
Torres-Cabala
Carlos
C
Yang
Youfeng
Y
Schmidt
Laura
L
Walther
McClellan
M
Linehan
W Marston
WM
D051792:Basic Helix-Loop-Helix Proteins; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics*; D007672:Kidney Cortex; D007680:Kidney Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1