Acker Till, Diez-Juan Antonio, Aragones Julian, Tjwa Marc, Brusselmans Koen, Moons Lieve, Fukumura Dai, Moreno-Murciano Maria Paz, Herbert Jean-Marc, Burger Angelika, Riedel Johanna, Elvert Gerd, Flamme Ingo, Maxwell Patrick H, Collen Désiré, Dewerchin Mieke, Jain Rakesh K, Plate Karl H, Carmeliet Peter
Edinger Institute, Neuropathology, Johann Wolfgang Goethe University, 60528 Frankfurt, Germany.
Cancer Cell. 2005 Aug;8(2):131-41. doi: 10.1016/j.ccr.2005.07.003.
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.
缺氧诱导转录因子HIF-1α和HIF-2α在缺氧肿瘤区域被激活。然而，它们在肿瘤发生中的作用仍存在争议，因为HIF-1α既有肿瘤生长促进作用又有抑制作用，而HIF-2α的作用在很大程度上仍不清楚。在此，我们表明，大鼠胶质瘤肿瘤中HIF-2α的过表达增强了血管生成，但部分通过增加肿瘤细胞凋亡而降低了这些肿瘤的生长。此外，HIF-2α的siRNA敲低减少了缺氧的人恶性胶质母细胞瘤细胞中的凋亡。此外，在胶质瘤细胞中通过显性负性HIF转基因的过表达或在畸胎瘤中HIF-2α缺陷来抑制HIF，减少了血管化，但加速了这些肿瘤类型的生长。这些发现促使人们在将HIF抑制剂用作癌症治疗策略时要谨慎考虑。
