Hypoxia induces protective autophagy in glioblastoma cells and new therapeutic avenues that target this process may improve the outcome for glioblastoma patients. Recent studies have suggested that the autophagic process is upregulated in glioblastomas in response to extensive hypoxia. Hypoxia also induces the upregulation of a specific set of proteins and microRNAs (miRNAs) in a variety of cell types. IL6 (interleukin 6), an inflammatory autocrine and paracrine cytokine that is overexpressed in glioblastoma, has been reported to be a biomarker for poor prognosis because of its tumor-promoting effects. Here, we describe a novel tumor-promoting mechanism of IL6, whereby hypoxia-induced IL6 acts as a potent initiator of autophagy in glioblastoma via the phosphorylated (p)-STAT3-MIR155-3p pathway. IL6 and p-STAT3 levels correlated with the abundance of autophagic cells and HIF1A levels in human glioma tissues and with the grade of human glioma, whereas inhibition of exogenous or endogenous IL6 repressed autophagy in glioblastoma cells in vitro. Knockdown of endogenous MIR155-3p inhibited IL6-induced autophagy, and enforced expression of MIR155-3p restored the anti-autophagic activity of IL6 inhibitors. We show that the hypoxia-IL6-p-STAT3-MIR155-3p-CREBRF-CREB3-ATG5 pathway plays a central role in malignant glioma progression, with blockade of the IL6 receptor by tocilizumab demonstrating a certain level of therapeutic efficacy in a xenograft model in vivo, especially in combination with temozolomide. Moreover, tocilizumab inhibits autophagy by promoting tumor apoptosis. Collectively, our findings provide new insight into the molecular mechanisms underlying hypoxia-induced glioma cell autophagy and point toward a possible efficacious adjuvant therapy for glioblastoma patients.
The delineation of brain gliomas margins still poses challenges to precise imaging and targeted therapy, mainly due to strong light attenuation of the skull and high background interference. With deep penetration and high sensitivity, photoacoustic (PA) imaging (PAI) in the second near‐infrared (NIR II) window holds great potential for brain gliomas imaging. Herein, mesoionic dye A1094 encapsulated in Arg‐Gly‐Asp‐modified hepatitis B virus core protein (RGD‐HBc) is designed and synthesized for effective NIR II PAI of brain gliomas. An aggregation‐induced absorption enhancement mechanism is discovered in vitro and in vivo. It is also demonstrated that A1094@RGD‐HBc, with an enhanced absorption in the NIR II window, displays ninefold PA signal amplification in vivo, allowing for precise PAI of the brain gliomas at a depth up to 5.9 mm. In addition, with the application of abovementioned agent, high‐resolution PAI and ultrasensitive single photon emission computed tomography images of brain gliomas are acquired with accurate co‐localization. Collectively, the results suggest great promise of A1094@RGD‐HBc for diagnostic imaging and precise delineation of brain gliomas in clinical applications.
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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