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.

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85. 85.

    Wu H, Wang F, Hu S, Yin C, Li X, Zhao S, Wang J, Yan X. MiR-20a and miR-106b negatively regulate autophagy induced by leucine deprivation via suppression of ULK1 expression in C2C12 myoblasts. Cell Signal 2012; 24:2179-86; PMID:22781751; http://dx.doi.org/

    Not in our library10.1016/j.cellsig.2012.07.001

86. 86.

    Zou Z, Wu L, Ding H, Wang Y, Zhang Y, Chen X, Chen X, Zhang CY, Zhang Q, Zen K. MicroRNA-30a sensitizes tumor cells to cis-platinum via suppressing beclin 1-mediated autophagy. J Biol Chem 2012; 287:4148-56; PMID:22157765; http://dx.doi.org/

    Not in our library10.1074/jbc.m111.307405

87. 87.

    Zhu H, Wu H, Liu X, Li B, Chen Y, Ren X, Liu CG, Yang JM. Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells. Autophagy 2009; 5:816-23; PMID:19535919; http://dx.doi.org/

    Not in our library10.4161/auto.9064

88. 88.

    Korkmaz G, le SC, Tekirdag KA, Agami R, Gozuacik D. miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1. Autophagy 2012; 8:165-76; PMID:22248718; http://dx.doi.org/

    Not in our library10.4161/auto.8.2.18351

89. 89.

    Huang Y, Guerrero-Preston R, Ratovitski EA. Phospho-DeltaNp63alpha-dependent regulation of autophagic signaling through transcription and micro-RNA modulation. Cell Cycle 2012; 11:1247-59; PMID:22356768; http://dx.doi.org/

    Not in our library10.4161/cc.11.6.19670

90. 90.

    Frankel LB, Wen J, Lees M, Hoyer-Hansen M, Farkas T, Krogh A, Jäättelä M, Lund AH. microRNA-101 is a potent inhibitor of autophagy. EMBO J 2011; 30:4628-41; PMID:21915098; http://dx.doi.org/

    Not in our library10.1038/emboj.2011.331

91. 91.

    Guo X, Xue H, Guo X, Gao X, Xu S, Yan S, Han X, Li T, Shen J, Li G. MiR224-3p inhibits hypoxia-induced autophagy by targeting autophagy-related genes in human glioblastoma cells. Oncotarget 2015; 39:41620–37; PMID:26536662; http://dx.doi.org/

    Not in our library10.18632/oncotarget.5871

92. 92.

    Fu LL, Wen X, Bao JK, Liu B. MicroRNA-modulated autophagic signaling networks in cancer. Int J Biochem Cell Biol 2012; 44:733-6; PMID:22342941; http://dx.doi.org/

    Not in our library10.1016/j.biocel.2012.02.004

93. 93.

    Frankel LB, Lund AH. MicroRNA regulation of autophagy. Carcinogenesis 2012; 33:2018-25; PMID:22902544; http://dx.doi.org/

    Not in our library10.1093/carcin/bgs266

94. 94.

    Fang Y, Xue JL, Shen Q, Chen J, Tian L. MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology 2012; 55:1852-62; PMID:22234835; http://dx.doi.org/

    Not in our library10.1002/hep.25576

95. 95.

    Ritchie W, Legendre M, Gautheret D. RNA stem-loops: to be or not to be cleaved by RNAse III. RNA 2007; 13:457-62; PMID:17299129; http://dx.doi.org/

    Not in our library10.1261/rna.366507

96. 96.

    Roy-Chaudhuri B, Valdmanis PN, Zhang Y, Wang Q, Luo QJ, Kay MA. Regulation of microRNA-mediated gene silencing by microRNA precursors. Nat Struct Mol Biol 2014; 21:825-32; PMID:25086740; http://dx.doi.org/

    Not in our library10.1038/nsmb.2862

97. 97.

    Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, Dreyfuss G, Eddy SR, Griffiths-Jones S, Marshall M, et al. A uniform system for microRNA annotation. RNA 2003; 9:277-9; PMID:12592000; http://dx.doi.org/

    Not in our library10.1261/rna.2183803

98. 98.

    Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 2011; 39:D152-7; PMID:21037258; http://dx.doi.org/

    Not in our library10.1093/nar/gkq1027

99. 99.

    Li P, Grgurevic S, Liu Z, Harris D, Rozovski U, Calin GA, Keating MJ, Estrov Z. Signal transducer and activator of transcription-3 induces microRNA-155 expression in chronic lymphocytic leukemia. PLoS One 2013; 8:e64678; PMID:23750211; http://dx.doi.org/

    Not in our library10.1371/journal.pone.0064678

100. 100.

     Elton TS, Selemon H, Elton SM, Parinandi NL. Regulation of the MIR155 host gene in physiological and pathological processes. Gene 2013; 532:1-12; PMID:23246696; http://dx.doi.org/

     Not in our library10.1016/j.gene.2012.12.009

101. 101.

     Chang Q, Daly L, Bromberg J. The IL-6 feed-forward loop: a driver of tumorigenesis. Semin Immunol 2014; 26:48-53; PMID:24613573; http://dx.doi.org/

     Not in our library10.1016/j.smim.2014.01.007

102. 102.

     Kojima T, Yabe Y, Kaneko A, Hirano Y, Ishikawa H, Hayashi M, Miyake H, Takagi H, Kato T, Terabe K, et al. Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis. Mod Rheumatol 2013; 23:977-85; PMID:23099471; http://dx.doi.org/

     Not in our library10.3109/s10165-012-0782-y

103. 103.

     Bay-Jensen AC, Platt A, Byrjalsen I, Vergnoud P, Christiansen C, Karsdal MA. Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium, cartilage, and bone in the LITHE study. Semin Arthritis Rheum 2014; 43:470-8; PMID:23932312; http://dx.doi.org/

     Not in our library10.1016/j.semarthrit.2013.07.008

104. 104.

     Shimamoto K, Ito T, Ozaki Y, Amuro H, Tanaka A, Nishizawa T, Son Y, Inaba M, Nomura S. Serum interleukin 6 before and after therapy with tocilizumab is a principal biomarker in patients with rheumatoid arthritis. J Rheumatol 2013; 40:1074-81; PMID:23637318; http://dx.doi.org/

     Not in our library10.3899/jrheum.121389

105. 105.

     Kasama T, Isojima S, Umemura M, Tsukamoto H, Tokunaga T, Furuya H, Yanai R, Takahashi R, Nakamura M, Inagaki K. Serum macrophage migration inhibitory factor levels are correlated with response to tocilizumab therapy in patients with rheumatoid arthritis. Rheumatol Int 2014; 34:429-33; PMID:23670804; http://dx.doi.org/

     Not in our library10.1007/s00296-013-2778-0

106. 106.

     Mittelbronn M, Platten M, Zeiner P, Dombrowski Y, Frank B, Zachskorn C, Harter PN, Weller M, Wischhusen J. Macrophage migration inhibitory factor (MIF) expression in human malignant gliomas contributes to immune escape and tumour progression. Acta Neuropathol 2011; 122:353-65; PMID:21773885; http://dx.doi.org/

     Not in our library10.1007/s00401-011-0858-3

107. 107.

     Wang XB, Tian XY, Li Y, Li B, Li Z. Elevated expression of macrophage migration inhibitory factor correlates with tumor recurrence and poor prognosis of patients with gliomas. J Neurooncol 2012; 106:43-51; PMID:21725855; http://dx.doi.org/

     Not in our library10.1007/s11060-011-0640-3

108. 108.

     Harris MG, Hulseberg P, Ling C, Karman J, Clarkson BD, Harding JS, Zhang M, Sandor A, Christensen K, Nagy A, et al. Immune privilege of the CNS is not the consequence of limited antigen sampling. Sci Rep 2014; 4:4422; PMID:24651727

     Not in our library10.1038/srep04422

109. 109.

     Weller M. More on the immune privilege of glioblastoma. Neuro Oncol 2012; 14:527-8; PMID:22539528; http://dx.doi.org/

     Not in our library10.1093/neuonc/nos110

110. 110.

     Galea I, Bechmann I, Perry VH. What is immune privilege (not). Trends Immunol 2007; 28:12-8; PMID:17129764; http://dx.doi.org/

     Not in our library10.1016/j.it.2006.11.004

111. 111.

     Mehling M, Simon P, Mittelbronn M, Meyermann R, Ferrone S, Weller M, Wiendl H. WHO grade associated downregulation of MHC class I antigen-processing machinery components in human astrocytomas: does it reflect a potential immune escape mechanism. Acta Neuropathol 2007; 114:111-9; PMID:17541610; http://dx.doi.org/

     Not in our library10.1007/s00401-007-0231-8

112. 112.

     Rossi ML, Esiri MM, Jones NR, Coakham HB, Moss TH, Cruz-Sanchez FF, Carey MP. Characterization of the mononuclear cell infiltrate and HLA-Dr expression in 19 oligodendrogliomas. Surg Neurol 1991; 36:119-25; PMID:1891756; http://dx.doi.org/

     Not in our library10.1016/0090-3019(91)90229-3

113. 113.

     Rebmann V, Regel J, Stolke D, Grosse-Wilde H. Secretion of sHLA-G molecules in malignancies. Semin Cancer Biol 2003; 13:371-7; PMID:14708717; http://dx.doi.org/

     Not in our library10.1016/s1044-579x(03)00028-2

114. 114.

     Wiendl H, Mitsdoerffer M, Hofmeister V, Wischhusen J, Bornemann A, Meyermann R, Weiss EH, Melms A, Weller M. A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol 2002; 168:4772-80; PMID:11971028; http://dx.doi.org/

     Not in our library10.4049/jimmunol.168.9.4772

115. 115.

     Albesiano E, Han JE, Lim M. Mechanisms of local immunoresistance in glioma. Neurosurg Clin N Am 2010; 21:17-29; PMID:19944963; http://dx.doi.org/

     Not in our library10.1016/j.nec.2009.08.008

116. 116.
     The Controversial Role of Microglia in Malignant Gliomas · 2013

     No notice
117. 117.

     Zhang J, Sarkar S, Cua R, Zhou Y, Hader W, Yong VW. A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis. Carcinogenesis 2012; 33:312-9; PMID:22159219; http://dx.doi.org/

     Not in our library10.1093/carcin/bgr289

118. 118.

     Komohara Y, Ohnishi K, Kuratsu J, Takeya M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 2008; 216:15-24; PMID:18553315; http://dx.doi.org/

     Not in our library10.1002/path.2370

119. 119.

     Serafini P, Borrello I, Bronte V. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 2006; 16:53-65; PMID:16168663; http://dx.doi.org/

     Not in our library10.1016/j.semcancer.2005.07.005

120. 120.

     Kieback DG, Press MF, Atkinson EN, Edwards GL, Mobus VJ, Runnebaum IB, Kreienberg R, Jones LA. Prognostic significance of estrogen receptor expression in ovarian cancer. Immunoreactive Score (IRS) vs. Composition Adjusted Receptor Level (CARL). Anticancer Res 1993; 13:2489-96; PMID:8135488

     Not in our library

121. 121.

     Friedrichs K, Gluba S, Eidtmann H, Jonat W. Overexpression of p53 and prognosis in breast cancer. Cancer 1993; 72:3641-7; PMID:8252480; http://dx.doi.org/

     Not in our library10.1002/1097-0142(19931215)72:12<3641::aid-cncr2820721215>3.0.co;2-8

Cited by papers we hold 9

• Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets · 2023
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• The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies · 2022
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• ELK3: A New Molecular Marker for the Diagnosis and Prognosis of Glioma · 2021
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• Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction · 2021
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• Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment · 2020
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• The Emerging Role of Myeloid-Derived Suppressor Cells in the Glioma Immune Suppressive Microenvironment · 2020
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• Overexpression of Limb-Bud and Heart (LBH) promotes angiogenesis in human glioma via VEGFA-mediated ERK signalling under hypoxia · 2019
  Not checked
• Autophagy and inflammation · 2017
  No notice
• Autophagy-Regulating microRNAs and Cancer · 2017
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Reads

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