Favier Judith, Lapointe Stéphanie, Maliba Ricardo, Sirois Martin G
Research Center, Montreal Heart Institute, Montreal, Québec, Canada.
BMC Cancer. 2007 Jul 26;7:139. doi: 10.1186/1471-2407-7-139.
HIF2alpha/EPAS1 is a hypoxia-inducible transcription factor involved in catecholamine homeostasis, vascular remodelling, physiological angiogenesis and adipogenesis. It is overexpressed in many cancerous tissues, but its exact role in tumour progression remains to be clarified.
In order to better establish its function in tumourigenesis and tumour angiogenesis, we have stably transfected mouse neuroblastoma N1E-115 cells with the native form of HIF2alpha or with its dominant negative mutant, HIF2alpha (1-485) and studied their phenotype in vitro and in vivo.
In vitro studies reveal that HIF2alpha induces neuroblastoma cells hypertrophy and decreases their proliferation rate, while its inactivation by the HIF2alpha (1-485) mutant leads to a reduced cell size, associated with an accelerated proliferation. However, our in vivo experiments show that subcutaneous injection of cells overexpressing HIF2alpha into syngenic mice, leads to the formation of tumour nodules that grow slower than controls, but that are well structured and highly vascularized. In contrast, HIF2alpha (1-485)-expressing neuroblastomas grow fast, but are poorly vascularized and quickly tend to extended necrosis.
Together, our data reveal an unexpected combination between an antiproliferative and a pro-angiogenic function of HIF2alpha that actually seems to be favourable to the establishment of neuroblastomas in vivo.
低氧诱导因子2α/内皮 PAS 结构域蛋白1（HIF2α/EPAS1）是一种低氧诱导转录因子，参与儿茶酚胺稳态、血管重塑、生理性血管生成和脂肪生成。它在许多癌组织中过表达，但其在肿瘤进展中的确切作用仍有待阐明。
为了更好地确定其在肿瘤发生和肿瘤血管生成中的功能，我们用天然形式的 HIF2α 或其显性负性突变体 HIF2α（1 - 485）稳定转染小鼠神经母细胞瘤 N1E - 115 细胞，并在体外和体内研究它们的表型。
体外研究表明，HIF2α 诱导神经母细胞瘤细胞肥大并降低其增殖速率，而其被 HIF2α（1 - 485）突变体失活导致细胞尺寸减小，同时增殖加速。然而，我们的体内实验表明，将过表达 HIF2α 的细胞皮下注射到同基因小鼠中，会导致肿瘤结节形成，其生长速度比对照组慢，但结构良好且血管高度丰富。相比之下，表达 HIF2α（1 - 485）的神经母细胞瘤生长迅速，但血管化程度低，且很快趋于广泛坏死。
总之，我们的数据揭示了 HIF2α 的抗增殖和促血管生成功能之间意想不到的组合，这实际上似乎有利于体内神经母细胞瘤的形成。
