Interference of macrophage migration inhibitory factor expression in a mouse melanoma inhibits tumor establishment by up-regulating thrombospondin-1
Interference of macrophage migration inhibitory factor expression in a mouse melanoma inhibits tumor establishment by up-regulating thrombospondin-1
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DOI：
10.1158/1541-7786.mcr-07-0229
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发表时间：
2007-12-01
影响因子：
5.2
通讯作者：
Garland, Donita
中科院分区：
文献类型：
--
作者：
Culp, W. David;Tsagozis, Panagiotis;Garland, Donita
巨噬细胞移动抑制因子（MIF）是一种多效细胞因子，具有促炎、促血管生成和促肿瘤发生的特性。MIF在肿瘤发生和血管生成中的作用的分子机制还不清楚。为了解决这些作用，干扰MIF（iMIF）RNA被稳定地引入到B16-F10小鼠黑色素瘤细胞系中，相对于对照细胞，MIF mRNA表达降低1.6倍，MIF蛋白表达降低2.8倍。当将iMIF细胞皮下注射到C57131 L/6小鼠中时，肿瘤建立显著延迟，并且相对于对照，iMIF肿瘤中明显缺乏瘤内脉管系统。iMIF和对照黑色素瘤细胞系的比较基因表达分析显示，通过实时PCR，血小板反应蛋白-1（TSP-1）mRNA表达在iMIF细胞中上调88倍。在iMIF细胞培养上清液中观察到TSP-1蛋白水平增加2倍。这些结果强烈表明，iMIF黑色素瘤中延迟的肿瘤建立和减少的脉管系统与抗血管生成TSP-1的上调有关。他们进一步定义了MIF作为小鼠黑色素瘤模型中TSP-1调节剂的新功能。
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with proinflammatory, proangiogenic, and protumorigenic properties. The molecular mechanisms underlying the role of MIF in tumorigenesis and angiogenesis are not well understood. To address these roles, an interfering MIF (iMIF) RNA was stably introduced into the B16-F10 mouse melanoma cell line, reducing MIF mRNA expression 1.6-fold and MIF protein expression 2.8-fold relative to control cells. When iMIF cells were subcutaneously injected into C57131L/6 mice, tumor establishment was significantly delayed and there was a marked absence of intratumoral vasculature in iMIF tumors relative to controls. A comparative gene expression analysis of iMIF and control melanoma cell lines revealed that thrombospondin-1 (TSP-1) mRNA expression was up-regulated 88-fold in the iMIF cells by real-time PCR. A 2-fold increase in TSP-1 protein levels was observed in iMIF cell culture supernatants. These results strongly suggest that the delayed tumor establishment and reduced vasculature in iMIF melanomas are linked to the up-regulation of the antiangiogenic TSP-1. They further define a novel function of MIF as a regulator of TSP-1 in a mouse melanoma model.