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Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1 alpha in clear cell renal carcinomas.
5215 - 5222.
The transcription factor hypoxia-inducible factor (HIF)-1 is an important mediator of hypoxic adaptation of tumor cells and controls several genes that have been implicated in tumor growth. Oxygen-dependent degradation of HIF-1 alpha, the regulatory subunit, requires binding to the von Hippel Lindau (VHL) protein. Because functional inactivation of the VHL tumor suppressor gene occurs in up to 70% of clear cell renal carcinomas, we investigated whether this results in overexpression of HIF-1 alpha and its target genes, Immunoblotting revealed increased expression of HIF-1 alpha in 24 of 32 (75%) clear cell renal carcinomas but only 3 of 8 non-clear cell renal tumors. Somatic mutations of the VHL gene were detected only in clear cell renal carcinomas that overexpressed HIF-1 alpha, None of the HIF-1 alpha -negative tumors displayed a VHL mutation. The level of HIF-1 alpha mRNA was not different between tumors and adjacent kidney tissue. Immunohistochemistry revealed distinct patterns of nuclear staining for HIF-1 alpha, depending on histological type and overall abundance of HIF-1 alpha, In those clear cell renal carcinomas that showed increased expression on immunoblots, HIF-1 alpha was expressed in almost all cells. In the remaining clear cell and in non-clear cell tumors, staining was focal; these different patterns thus were compatible with genetic stabilization in contrast to microenvironmental stimulation of HIF-1 alpha as the primary mechanism. The mRNA expression of two known target genes of HIF-1 alpha, vascular endothelial growth factor and glucose transporter 1, increased progressively with increasing amounts of HIF-1 alpha in tumor extracts. In addition, glucose transporter 1 protein levels correlated with HIF-1 alpha abundance, In conclusion, the data provide in vivo evidence for a constitutive up-regulation of HIF-1 alpha in the majority of clear cell renal carcinomas, which leads to more widespread accumulation of this transcription factor than hypoxic stimulation. These observations are most likely linked to functional inactivation of the VHL gene product. Increased expression of HIF-1 alpha is associated with alterations in gene expression patterns that are likely to contribute to tumor phenotype and progression.
|Title:||Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1 alpha in clear cell renal carcinomas|
|Keywords:||ENDOTHELIAL GROWTH-FACTOR, TUMOR-SUPPRESSOR GENE, UBIQUITIN-PROTEASOME PATHWAY, HIPPEL-LINDAU PROTEIN, FACTOR 1-ALPHA, FACTORS HIF-1-ALPHA, NORMOXIC CONDITIONS, SOMATIC MUTATIONS, UP-REGULATION, FACTOR-I|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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