A novel tumor-promoting mechanism of IL6 and the therapeutic efficacy of tocilizumab: Hypoxia-induced IL6 is a potent autophagy initiator in glioblastoma via the p-STAT3-MIR155-3p-CREBRF pathway.
A novel tumor-promoting mechanism of IL6 and the therapeutic efficacy of tocilizumab: Hypoxia-induced IL6 is a potent autophagy initiator in glioblastoma via the p-STAT3-MIR155-3p-CREBRF pathway.
复制标题
IL6 的新型肿瘤促进机制和托珠单抗的治疗功效：缺氧诱导的 IL6 通过 p-STAT3-MIR155-3p-CREBRF 途径是胶质母细胞瘤中有效的自噬引发剂
DOI：
10.1080/15548627.2016.1178446
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发表时间：
2016-07-02
期刊：
影响因子：
13.3
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Xue H;Yuan G;Guo X;Liu Q;Zhang J;Gao X;Guo X;Xu S;Li T;Shao Q;Yan S;Li G
摘要 缺氧会诱导胶质母细胞瘤细胞发生保护性自噬，针对这一过程的新治疗途径可能会改善胶质母细胞瘤患者的预后。最近的研究表明，胶质母细胞瘤中的自噬过程因广泛缺氧而上调。缺氧还会诱导多种细胞类型中一组特定蛋白质和 microRNA (miRNA) 的上调。 IL6（白细胞介素 6）是一种在胶质母细胞瘤中过度表达的炎症性自分泌和旁分泌细胞因子，据报道，由于其促肿瘤作用，它是预后不良的生物标志物。在这里，我们描述了 IL6 的一种新的肿瘤促进机制，其中缺氧诱导的 IL6 通过磷酸化 (p)-STAT3-MIR155-3p 途径充当胶质母细胞瘤中自噬的有效引发剂。 IL6和p-STAT3水平与人胶质瘤组织中自噬细胞的丰度和HIF1A水平以及人胶质瘤的分级相关，而外源性或内源性IL6的抑制可抑制体外胶质母细胞瘤细胞的自噬。内源性 MIR155-3p 的敲低可抑制 IL6 诱导的自噬，而 MIR155-3p 的强制表达可恢复 IL6 抑制剂的抗自噬活性。我们发现缺氧-IL6-p-STAT3-MIR155-3p-CREBRF-CREB3-ATG5通路在恶性胶质瘤进展中发挥核心作用，托珠单抗对IL6受体的阻断在体内异种移植模型中表现出一定水平的治疗效果，特别是与替莫唑胺联合使用。此外，托珠单抗通过促进肿瘤细胞凋亡来抑制自噬。总的来说，我们的研究结果为缺氧诱导的胶质瘤细胞自噬的分子机制提供了新的见解，并为胶质母细胞瘤患者提供了可能有效的辅助治疗。
ABSTRACT 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.