Genetic evidence for a tumor suppressor role of HIF-2α

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.

Hypoxia-associated markers in gastric carcinogenesis and HIF-2α in gastric and gastro-oesophageal cancer prognosis

“…Hypoxia-inducible factor-2a expression has not been studied in models of tumour carcinogenesis except in our work in the Barrett's metaplasia -dysplasia -adenocarcinoma sequence, where we showed that HIF-2a was expressed late in the sequence and was seen only in dysplasia and adenocarcinoma (Griffiths et al, 2007a). Recently, the overexpression of HIF-2a in rat gliomas was shown to have counteracting properties, in which angiogenesis was induced but reduced growth was also found due to increased tumour-cell apoptosis (Acker et al, 2005). Hypoxiainducible factor-2a expression has also been suggested to be critical in the carcinogenesis of renal cortical tumours (Kim et al, 2006).…”

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

“…In addition one should stress that the therapeutic use of angiogenesis inhibitors, including VEGF and prolyl hydroxylase antagonists, is likely to TEL-ARNT interferes with cellular differentiation F Nguyen-Khac et al exhibit deleterious effects both on normal differentiation and malignant cell transformation (Acker et al, 2005).…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…Based on published data, the role of HIF-2α in glioblastoma formation and aggressiveness is not fully clear, as HIF-2α has been attributed a tumor-suppressor role (Acker et al 2005), as well as being a marker for poor prognosis ). Overexpression of HIF-2α protein in rat glioblastomas suppressed tumor growth despite overall enhanced vascularization.…”

“…Overexpression of HIF-2α protein in rat glioblastomas suppressed tumor growth despite overall enhanced vascularization. This was in part explained by increased tumor cell apoptosis, and knockdown of HIF-2α in hypoxic human glioblastoma cells reduced the apoptotic rate of these cells (Acker et al 2005). Recent work on GBM has focused highly on the small fraction of tumor cells with stem cell characteristics that are thought to initiate and maintain tumor growth (Hemmati et al 2003;Singh et al 2003;Galli et al 2004;Singh et al 2004).…”