MIF Maintains the Tumorigenic Capacity of Brain Tumor-Initiating Cells by Directly Inhibiting p53
MIF Maintains the Tumorigenic Capacity of Brain Tumor-Initiating Cells by Directly Inhibiting p53
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DOI：
10.1158/0008-5472.can-15-1011
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发表时间：
2016-05-01
期刊：
影响因子：
11.2
通讯作者：
Toda, Masahiro
中科院分区：
文献类型：
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作者：
Fukaya, Raita;Ohta, Shigeki;Toda, Masahiro
被认为是驱动脑癌的肿瘤起始细胞嵌入复杂的异质组织中。在这项研究中，我们从21例人脑肿瘤标本中分离出原代细胞，以建立具有高致瘤潜力的细胞系，并鉴定使这种能力的分子。所有细胞系的形态、扩增后的球体形成能力和分化潜能在体外无法区分。然而，致瘤性测试揭示了两种不同的细胞类型，脑肿瘤起始细胞（BTIC）和非BTIC。我们发现巨噬细胞移动抑制因子（MIF）在BTIC中的表达高于非BTIC。MIF直接与野生型和突变型p53结合，但通过不同的机制调节p53依赖的细胞生长，这取决于胶质瘤细胞系和p53状态。MIF与细胞核中的野生型p53发生物理相互作用，并抑制其转录依赖性功能。与此相反，MIF绑定到突变型p53在细胞质中，并废除转录非依赖性诱导细胞凋亡。此外，在小鼠异种移植模型中，MIF敲低抑制BTIC诱导的肿瘤形成，导致总存活率增加。总的来说，我们的研究结果表明，MIF调节BTIC功能，通过直接，细胞内抑制p53，揭示了某些恶性脑细胞的致瘤性的分子机制。(C)2016年AACR。
Tumor-initiating cells thought to drive brain cancer are embedded in a complex heterogeneous histology. In this study, we isolated primary cells from 21 human brain tumor specimens to establish cell lines with high tumorigenic potential and to identify the molecules enabling this capability. The morphology, sphere-forming ability upon expansion, and differentiation potential of all cell lines were indistinguishable in vitro. However, testing for tumorigenicity revealed two distinct cell types, brain tumor-initiating cells (BTIC) and non-BTIC. We found that macrophage migration inhibitory factor (MIF) was highly expressed in BTIC compared with non-BTIC. MIF bound directly to both wild-type and mutant p53 but regulated p53-dependent cell growth by different mechanisms, depending on glioma cell line and p53 status. MIF physically interacted with wild-type p53 in the nucleus and inhibited its transcription-dependent functions. In contrast, MIF bound to mutant p53 in the cytoplasm and abrogated transcription-independent induction of apoptosis. Furthermore, MIF knockdown inhibited BTIC-induced tumor formation in a mouse xenograft model, leading to increased overall survival. Collectively, our findings suggest that MIF regulates BTIC function through direct, intracellular inhibition of p53, shedding light on the molecular mechanisms underlying the tumorigenicity of certain malignant brain cells. (C) 2016 AACR.