Brain Miffed by Macrophage Migration Inhibitory Factor

Savaskan, Nicolai Ε.; Fingerle‐Rowson, Günter; Buchfelder, Michael; Eyüpoglu, Ilker Y.

doi:10.1155/2012/139573

Cited by 30 publications

(20 citation statements)

References 112 publications

(139 reference statements)

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“…MIF upregulation has been observed in human melanoma (19), lung cancer (20), prostate cancer (21), hepatocellular carcinoma (22), and glioblastoma (23)(24)(25)(26)(27). MIF expression was significantly higher in the tumor tissues of glioblastoma patients than in normal brain tissues (24,25).…”

Section: Introductionmentioning

confidence: 99%

MIF Maintains the Tumorigenic Capacity of Brain Tumor–Initiating Cells by Directly Inhibiting p53

et al. 2016

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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, sphereforming ability upon expansion, and differentiation potential of all cell lines were indistinguishable in vitro. However, testing for tumorigenicity revealed two distinct cell types, brain tumorinitiating 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. Cancer Res; 76(9); 2813-23. Ó2016AACR.

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Section: Introductionmentioning

confidence: 99%

MIF Maintains the Tumorigenic Capacity of Brain Tumor–Initiating Cells by Directly Inhibiting p53

et al. 2016

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“…Studies of MIF function in animals suggest that this factor may play additional unknown roles in other diseases. In the central nervous system (CNS), MIF expression has been reported in the rat forebrain ventricular zone [5], yet the function of MIF in the CNS and in NSPCs had not yet been clarified [6]. We previously reported that MIF supports the proliferation and/or survival of murine NSPCs in vitro [7].…”

Section: Introductionmentioning

confidence: 99%

CHD7 promotes proliferation of neural stem cells mediated by MIF

et al. 2016

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Macrophage migration inhibitory factor (MIF) plays an important role in supporting the proliferation and/or survival of murine neural stem/progenitor cells (NSPCs); however, the downstream effectors of this factor remain unknown. Here, we show that MIF increases the expression of Pax6 and Chd7 in NSPCs in vitro. During neural development, the chromatin remodeling factor Chd7 (chromatin helicase-DNA-binding protein 7) is expressed in the ventricular zone of the telencephalon of mouse brain at embryonic day 14.5, as well as in cultured NSPCs. Retroviral overexpression of Pax6 in NSPCs increased Chd7 gene expression. Lentivirally-expressed Chd7 shRNA suppressed cell proliferation and neurosphere formation, and inhibited neurogenesis in vitro, while decreasing gene expression of Hes5 and N-myc. In addition, CHD7 overexpression increased cell proliferation in human embryonic stem cell-derived NSPCs (ES-NSPCs). In Chd7 mutant fetal mouse brains, there were fewer intermediate progenitor cells (IPCs) compared to wildtype littermates, indicating that Chd7 contributes to neurogenesis in the early developmental mouse brain. Furthermore, in silico database analysis showed that, among members of the CHD family, CHD7 is highly expressed in human gliomas. Interestingly, high levels of CHD7 gene expression in human glioma initiating cells (GICs) compared to normal astrocytes were revealed and gene silencing of CHD7 decreased GIC proliferation. Collectively, our data demonstrate that CHD7 is an important factor in the proliferation and stemness maintenance of NSPCs, and CHD7 is a promising therapeutic target for the treatment of gliomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0275-6) contains supplementary material, which is available to authorized users.

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“…MIF expression can also affect adult neurogenesis, as well as learning and memory, and depression [58]. Within the central nervous system (CNS), astrocytes are the major site of MIF expression [59], while the major site of MIF action is at CXCR2 on macrophages and microglia [60]. Likewise, in the CNS, TNF-α is produced by astrocytes and microglia [61].…”

Section: Discussionmentioning

confidence: 99%