Genetic evidence for a tumor suppressor role of HIF-2alpha.

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.

• Authors: Till Acker, Antonio Diez-Juan, Julian Aragones, Marc Tjwa, Koen Brusselmans, Lieve Moons, Dai Fukumura, Maria Paz Moreno-Murciano, Jean-Marc Herbert, Angelika Burger, Johanna Riedel, Gerd Elvert, Ingo Flamme, Patrick H Maxwell, Désiré Collen, Mieke Dewerchin, Rakesh K Jain, Karl H Plate, Peter Carmeliet
• Journal: Cancer cell (Cancer Cell) Vol. 8 Issue 2 Pg. 131-41 (Aug 2005) ISSN: 1535-6108 [Print] United States
• PMID: 16098466 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• RNA, Small Interfering
• Transcription Factors
• Tumor Suppressor Proteins
• endothelial PAS domain-containing protein 1

Topics

• Animals
• Apoptosis
• Basic Helix-Loop-Helix Transcription Factors
• Glioma (blood supply, genetics, metabolism)
• Humans
• Mice
• Neoplasms, Neuroepithelial (blood supply, genetics, metabolism)
• Neovascularization, Pathologic (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Rats
• Transcription Factors (antagonists & inhibitors, genetics, physiology)
• Transcriptional Activation
• Tumor Suppressor Proteins (antagonists & inhibitors, genetics, physiology)