Oncotarget

Research Papers:

Macrophage migration inhibitory factor promotes vasculogenic mimicry formation induced by hypoxia via CXCR4/AKT/EMT pathway in human glioblastoma cells

Xing Guo, Shugang Xu, Xiao Gao, Jian Wang, Hao Xue, Zihang Chen, Jinsen Zhang, Xiaofan Guo, Mingyu Qian, Wei Qiu and Gang Li _

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Oncotarget. 2017; 8:80358-80372. https://doi.org/10.18632/oncotarget.18673

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Abstract

Xing Guo1, Shugang Xu1,4, Xiao Gao1, Jian Wang1,2,3, Hao Xue1, Zihang Chen1, Jinsen Zhang1, Xiaofan Guo1, Mingyu Qian1, Wei Qiu1 and Gang Li1,2

1Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China

2Brian Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China

3Department of Biomedicine, University of Bergen, 5009-Bergen, Norway

4Department of Neurosurgery, Dezhou People’s Hospital, Dezhou, Shandong Province, P.R. China

Correspondence to:

Gang Li, email: ligangqiluhospital@163.com

Keywords: hypoxia, vasculogenic mimicry, MIF, CXCR4, glioblastoma

Received: August 24, 2016    Accepted: May 08, 2017    Published: June 27, 2017

ABSTRACT

Macrophage migration inhibitory factor (MIF) is over-expressed and secreted in various cancer cells in particular in response to hypoxia. Recent studies have shown that, under hypoxic conditions, glioblastoma (GBM) cells display the ability to drive blood-perfused vasculogenic mimicry (VM). The aim of this study was to investigate the underlying mechanism of MIF in the regulation of hypoxia-induced VM in GBM cells. By analyzing clinical specimens, we observed the co-localization of MIF, C-X-C motif chemokine receptor 4 (CXCR4) and VM in hypoxic regions of gliomas. In vitro, the exposure of GBM cells (U87 and U251) to hypoxia increased the expression of MIF and CXCR4 and induced VMs. Other data demonstrated that ectogenic rhMIF promoted VMs in GBM cells and knock-down endogenous MIF attenuated hypoxia-induced VMs. In addition, we demonstrated that MIF augmented VM formation ability by enhancing the epithelial mesenchymal transition (EMT) through the CXCR4-AKT pathway. Moreover, in vivo, the subcutaneous injection of rhMIF resulted in the progression of EMT and VMs formation. On the contrary, CXCR4-AKT pathway inhibitors blocked the effects of rhMIF on EMT and VMs formation. Collectively, our results support a critical role for the MIF-CXCR4 signaling axis in regulating hypoxia-induced VMs formation, indicating the potential usefulness of MIF as a notable target for the anti-vascularization treatment of GBM.


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