Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype
Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype
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DOI：
10.1073/pnas.102660199
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发表时间：
2002-05-14
影响因子：
11.1
通讯作者：
Påhlman, S
中科院分区：
文献类型：
--
作者：
Jögi, A;Ora, I;Påhlman, S
氧气和营养供应不足通常会抑制实体瘤的生长，缺氧诱导因子 (HIF) 1α 和 HIF-2α 是表型适应低氧水平的关键转录调节因子。此外，小鼠基因破坏研究表明 HIF-2α 与酪氨酸羟化酶（交感神经系统的标志基因）的胚胎调节有关。神经母细胞瘤起源于未成熟的交感神经细胞，因此我们研究了缺氧对人神经母细胞瘤细胞分化状态的影响。缺氧稳定了 HIF-1α 和 HIF-2α 蛋白，并激活了已知缺氧诱导基因的表达，例如血管内皮生长因子和酪氨酸羟化酶。这些基因表达的变化也发生在小鼠实验性神经母细胞瘤异种移植物的缺氧区域。相反，缺氧降低了一些神经元/神经内分泌标记基因的表达，但诱导了神经嵴交感神经祖细胞中表达的基因，例如c-kit和Notch-1。因此，缺氧显然会导致体外和体内的去分化。这些发现提出了一种选择具有干细胞特征的高度恶性肿瘤细胞的新机制。
Insufficient oxygen and nutrient supply often restrain solid tumor growth, and the hypoxia-inducible factors (HIF) 1alpha and HIF-2alpha are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated HIF-2alpha in embryonic regulation of tyrosine hydroxylase, a hallmark gene of the sympathetic nervous system. Neuroblastoma tumors originate from immature sympathetic cells, and therefore we investigated the effect of hypoxia on the differentiation status of human neuroblastoma cells. Hypoxia stabilized HIF-1alpha and HIF-2alpha proteins and activated the expression of known hypoxia-induced genes, such as vascular endothelial growth factor and tyrosine hydroxylase. These changes in gene expression also occurred in hypoxic regions of experimental neuroblastoma xenografts grown in mice. In contrast, hypoxia decreased the expression of several neuronal/neuroendocrine marker genes but induced genes expressed in neural crest sympathetic progenitors, for instance c-kit and Notch-1. Thus, hypoxia apparently causes dedifferentiation both in vitro and in vivo. These findings suggest a novel mechanism for selection of highly malignant tumor cells with stem-cell characteristics.