title: 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.
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.
authors.affiliation: a Department of Neurosurgery , Qilu Hospital of Shandong University , Jinan , Shandong Province , China.|b Brain Science Research Institute, Shandong University , Jinan , Shandong Province , China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xue
authors.affiliation: c Department of Neurosurgery , Central Hospital of Zibo City , Zibo , Shandong Province , China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yuan
authors.affiliation: a Department of Neurosurgery , Qilu Hospital of Shandong University , Jinan , Shandong Province , China.|b Brain Science Research Institute, Shandong University , Jinan , Shandong Province , China.
authors.forename: Xing
authors.initials: X
authors.lastname: Guo
authors.affiliation: a Department of Neurosurgery , Qilu Hospital of Shandong University , Jinan , Shandong Province , China.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: a Department of Neurosurgery , Qilu Hospital of Shandong University , Jinan , Shandong Province , China.|b Brain Science Research Institute, Shandong University , Jinan , Shandong Province , China.
authors.forename: Jinsen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: a Department of Neurosurgery , Qilu Hospital of Shandong University , Jinan , Shandong Province , China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Gao
authors.affiliation: a Department of Neurosurgery , Qilu Hospital of Shandong University , Jinan , Shandong Province , China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Guo
authors.affiliation: a Department of Neurosurgery , Qilu Hospital of Shandong University , Jinan , Shandong Province , China.|d Department of Neurosurgery , Dezhou People's Hospital , Dezhou , Shandong Province , China.
authors.forename: Shugang
authors.initials: S
authors.lastname: Xu
authors.affiliation: a Department of Neurosurgery , Qilu Hospital of Shandong University , Jinan , Shandong Province , China.
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.affiliation: e Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University , Jinan , Shandong Province , China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Shao
authors.affiliation: b Brain Science Research Institute, Shandong University , Jinan , Shandong Province , China.
authors.forename: Shaofeng
authors.initials: S
authors.lastname: Yan
authors.affiliation: a Department of Neurosurgery , Qilu Hospital of Shandong University , Jinan , Shandong Province , China.|b Brain Science Research Institute, Shandong University , Jinan , Shandong Province , China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology*; D001932:Brain Neoplasms / Q000473:pathology; D002273:Carcinogens / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051017:Apoptosis Regulatory Proteins; C000617553:CREB3 regulatory factor, human; D002273:Carcinogens; C508600:IL6 protein, human; D015850:Interleukin-6; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D025521:Tumor Suppressor Proteins; C502936:tocilizumab
keywords: ATG5; CREB3; CREBRF; IL6; STAT3; autophagy; glioblastoma; hypoxia; microRNAs; tocilizumab