Genetic evidence for a tumor suppressor role of HIF-2alpha.
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.
Acker
Till
T
Edinger Institute, Neuropathology, Johann Wolfgang Goethe University, 60528 Frankfurt, Germany. till.acker@med.uni-frankfurt.de
Diez-Juan
Antonio
A
Aragones
Julian
J
Tjwa
Marc
M
Brusselmans
Koen
K
Moons
Lieve
L
Fukumura
Dai
D
Moreno-Murciano
Maria Paz
MP
Herbert
Jean-Marc
JM
Burger
Angelika
A
Riedel
Johanna
J
Elvert
Gerd
G
Flamme
Ingo
I
Maxwell
Patrick H
PH
Collen
Désiré
D
Dewerchin
Mieke
M
Jain
Rakesh K
RK
Plate
Karl H
KH
Carmeliet
Peter
P
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D005910:Glioma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018302:Neoplasms, Neuroepithelial / Q000098:blood supply / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1