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

Abstract

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.

CHD7 promotes proliferation of neural stem cells mediated by MIF

“…GICs are known to maintain glioma, and the identification of key molecule(s) in the regulation of GICs may contribute to the development of novel glioma treatment strategies [9]. To test the function of CHD7 in human glioma, we firstly examined the CHD7 gene expression in normal astrocytes, NSPCs (human fetal brain derived), glioma cells (U87MG, U251), and GICs.…”

“…We reported the TP53 regulation by MIF in a transcription independent manner in human glioma cells [9]. Intriguingly, MIF was expressed in nucleus and cytoplasmic fractions and antagonized TP53 intracellularly in the system studied.…”

“…Human GICs were obtained as described previously [23]. Human astrocytes, U87MG, U251 and NSPCs were cultured as reported by Fukaya et al, [9]. The study using human NSPCs was carried out in accordance with the principles of the Helsinki Declaration, and the Japan Society of Obstetrics and Gynecology.…”

“…We have also identified Sox6 as a MIF downstream signaling molecule in mouse NSPCs [8]. We also recently reported that MIF supports the proliferation of GICs through TP53 regulation [9]. …”

Toll-like Receptors Regulate MIF Expression in Benign Lymphoepithelial Lesion of the Lacrimal Gland

“…Recently, our team showed that the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) is overexpressed in the plasma of BLEL patients [4], however, the causes of this deregulated expression remained unclear. MIF is a pleiotropic pro-inflammatory cytokine implicated in the pathogenesis of several inflammatory disorders, autoimmune diseases and tumors [5][6][7]. MIF is synthesized and stored in the cytoplasm of many cells [8,9] and is released in response to various stimuli including Toll-like receptors (TLRs) engagement with their specific ligands [10].…”