Winner Millicent, Koong Albert C, Rendon Beatriz E, Zundel Wayne, Mitchell Robert A
Molecular Targets Program, James Graham Brown Cancer Center and Department of Radiation Oncology, University of Louisville, 580 South Preston Street, Louisville, KY, USA.
Cancer Res. 2007 Jan 1;67(1):186-93. doi: 10.1158/0008-5472.CAN-06-3292.
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.
据报道，缺氧诱导因子（HIF）介导的低氧张力转录促进肿瘤进展、治疗抵抗和转移适应。先前描述的缺氧介导转录的一个靶点是细胞因子/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，MIF不仅在胰腺腺癌中由缺氧诱导，而且MIF对于最大程度的缺氧诱导的HIF-1α表达也是必需的。缺乏MIF的细胞在缺氧和脯氨酰羟化酶抑制剂诱导的HIF-1α稳定以及随后的糖酵解和血管生成基因产物转录方面存在缺陷。此外，COP9信号体亚基5（CSN5）是先前报道的与MIF在功能上相互作用的COP9信号体的一个组成部分，最近已显示其与HIF-1α相互作用并使其稳定。我们的结果表明，MIF在胰腺癌细胞中与CSN5相互作用，且MIF缺失的细胞在缺氧诱导的CSN5/HIF-1α相互作用中表现出明显缺陷。HIF-1α与MIF之间的这种功能相互依赖可能代表了一个重要且先前未被认识的促肿瘤轴。
