Abstract
The hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha are activated in hypoxic tumor regions. However, their role in tumorigenesis remains controversial, as tumor growth promoter and suppressor activities have been ascribed to HIF-1alpha, while the role of HIF-2alpha remains largely unknown. Here, we show that overexpression of HIF-2alpha in rat glioma tumors enhances angiogenesis but reduces growth of these tumors, in part by increasing tumor cell apoptosis. Moreover, siRNA knockdown of HIF-2alpha reduced apoptosis in hypoxic human malignant glioblastoma cells. Furthermore, inhibition of HIF by overexpression of a dominant-negative HIF transgene in glioma cells or HIF-2alpha deficiency in teratomas reduced vascularization but accelerated growth of these tumor types. These findings urge careful consideration of using HIF inhibitors as cancer therapeutic strategies.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Apoptosis
-
Basic Helix-Loop-Helix Transcription Factors
-
Glioma / blood supply*
-
Glioma / genetics
-
Glioma / metabolism
-
Humans
-
Mice
-
Neoplasms, Neuroepithelial / blood supply
-
Neoplasms, Neuroepithelial / genetics
-
Neoplasms, Neuroepithelial / metabolism
-
Neovascularization, Pathologic* / genetics
-
Neovascularization, Pathologic* / metabolism
-
RNA, Small Interfering / genetics
-
Rats
-
Transcription Factors / antagonists & inhibitors
-
Transcription Factors / genetics
-
Transcription Factors / physiology*
-
Transcriptional Activation
-
Tumor Suppressor Proteins / antagonists & inhibitors
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / physiology*
Substances
-
Basic Helix-Loop-Helix Transcription Factors
-
RNA, Small Interfering
-
Transcription Factors
-
Tumor Suppressor Proteins
-
endothelial PAS domain-containing protein 1