Culp W David, Tsagozis Panagiotis, Burgio Michael, Russell Paul, Pisa Pavel, Garland Donita
National Eye Institute, Bethesda, MD, USA.
Mol Cancer Res. 2007 Dec;5(12):1225-31. doi: 10.1158/1541-7786.MCR-07-0229.
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 C57BL/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.
巨噬细胞移动抑制因子（MIF）是一种具有促炎、促血管生成和促肿瘤特性的多效细胞因子。MIF在肿瘤发生和血管生成中作用的分子机制尚未完全明确。为了研究这些作用，将干扰性MIF（iMIF）RNA稳定导入B16-F10小鼠黑色素瘤细胞系，相对于对照细胞，iMIF mRNA表达降低了1.6倍，MIF蛋白表达降低了2.8倍。将iMIF细胞皮下注射到C57BL/6小鼠体内时，肿瘤形成明显延迟，相对于对照，iMIF肿瘤内明显缺乏肿瘤内血管。对iMIF和对照黑色素瘤细胞系进行的比较基因表达分析显示，通过实时PCR，iMIF细胞中血小板反应蛋白-1（TSP-1）mRNA表达上调了88倍。在iMIF细胞培养上清液中观察到TSP-1蛋白水平增加了2倍。这些结果强烈表明，iMIF黑色素瘤中肿瘤形成延迟和血管减少与抗血管生成TSP-1的上调有关。它们进一步确定了MIF在小鼠黑色素瘤模型中作为TSP-1调节剂的新功能。
