Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization.
Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization.
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DOI：
10.1158/0008-5472.can-06-3292
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发表时间：
2007
期刊：
影响因子：
11.2
通讯作者：
Millicent Winner;A. Koong;B. Rendon;W. Zundel;R. Mitchell
中科院分区：
文献类型：
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作者：
Millicent Winner;A. Koong;B. Rendon;W. Zundel;R. Mitchell
低氧诱导因子（HIF）介导的低氧张力转录已被报道促进肿瘤进展、治疗抗性和转移适应。一种先前描述的低氧介导的转录的靶标是细胞因子/生长因子巨噬细胞迁移抑制因子（MIF）。在旨在更好地理解缺氧刺激的MIF功能的研究中，我们发现，缺氧不仅诱导了胰腺癌中的MIF，而且MIF也是缺氧诱导的最大HIF-1 α表达所必需的。缺乏MIF的细胞在缺氧和脯氨酰羟化酶激动剂诱导的HIF-1 α稳定化和随后的糖酵解和血管生成基因产物的转录中有缺陷。此外，COP 9信号体亚基5（CSN 5），以前报道与MIF功能性相互作用的COP 9信号体的一个组分，最近已被证明与HIF-1 α相互作用并稳定HIF-1 α。我们的研究结果表明，在胰腺癌细胞中，MIF与CSN 5相互作用，并且MIF缺失的细胞在缺氧诱导的CSN 5/HIF-1 α相互作用中显示出明显的缺陷。HIF-1 α和MIF之间的这种功能相互依赖性可能代表了一个重要的和以前未被认识到的促肿瘤发生轴。
Low oxygen tension-mediated transcription by hypoxia-inducible factors (HIF) has been reported to facilitate tumor progression, therapeutic resistance, and metastatic adaptation. One previously described target of hypoxia-mediated transcription is the cytokine/growth factor macrophage migration inhibitory factor (MIF). In studies designed to better understand hypoxia-stimulated MIF function, we have discovered that not only is MIF induced by hypoxia in pancreatic adenocarcinoma but MIF is also necessary for maximal hypoxia-induced HIF-1alpha expression. Cells lacking MIF are defective in hypoxia- and prolyl hydroxylase inhibitor-induced HIF-1alpha stabilization and subsequent transcription of glycolytic and angiogenic gene products. Moreover, COP9 signalosome subunit 5 (CSN5), a component of the COP9 signalosome previously reported to functionally interact with MIF, has recently been shown to interact with and stabilize HIF-1alpha. Our results indicate that MIF interacts with CSN5 in pancreatic cancer cells and that MIF-depleted cells display marked defects in hypoxia-induced CSN5/HIF-1alpha interactions. This functional interdependence between HIF-1alpha and MIF may represent an important and previously unrecognized pro-tumorigenic axis.