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Research ArticleOriginal Article

Neutrophil extracellular traps mediate the crosstalk between glioma progression and the tumor microenvironment via the HMGB1/RAGE/IL-8 axis

Caijun Zha, Xiangqi Meng, Lulu Li, Shan Mi, Da Qian, Ziwei Li, Pengfei Wu, Shaoshan Hu, Shihong Zhao, Jinquan Cai and Yanhong Liu
Cancer Biology & Medicine February 2020, 17 (1) 154-168; DOI: https://doi.org/10.20892/j.issn.2095-3941.2019.0353
Caijun Zha
1Department of Laboratory Diagnosis, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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Xiangqi Meng
2Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
3Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
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Lulu Li
2Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
3Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
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Shan Mi
2Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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Da Qian
2Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
3Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
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Ziwei Li
2Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
3Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
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Pengfei Wu
2Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
3Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
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Shaoshan Hu
2Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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Shihong Zhao
2Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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Jinquan Cai
2Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
3Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
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  • ORCID record for Jinquan Cai
  • For correspondence: [email protected] [email protected]
Yanhong Liu
1Department of Laboratory Diagnosis, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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  • For correspondence: [email protected] [email protected]
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    Figure 1

    The infiltration of neutrophils and the formation of neutrophil extracellular traps (NETs) are associated with the malignancy of gliomas. (A) White blood cell counts of samples from healthy patients and patients with different WHO grades of gliomas. (B) Neutrophil cell counts of samples from healthy patients and patients with gliomas in different grades. (C) Kaplan–Meier survival analysis of patients with low neutrophil to lymphocyte ratio (NLR) and those with high NLR. (D) Neutrophil cell counts of samples with different immunohistochemistry (IHC) scores of NE. (E) IHC assays of CD66b, NE, and MPO in patients with different grades of gliomas (left panel), and corresponding IHC scores (right panel). (F) Immunofluorescence assays of MPO and citH3 in patients with different WHO grades of glioma. Significant results are presented as * P < 0.05, ** P < 0.01, or *** P < 0.001.

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    Figure 2

    Neutrophil extracellular traps (NETs) promote proliferation, migration, and invasion of glioblastoma cells. (A) Isolation of neutrophils from blood samples of healthy volunteers. (B) Immunofluorescence assay of the confirmation of NETs formation. (C) CCK-8 assays of glioma cells treated with neutrophils, NETs, or NETs combined with DNase I (NETs & DNase I). (D) Immunofluorescence assays of Ki67 in glioma cells treated with or without NETs. (E) Western blot validation of cyclin D1 and cyclin D2 in LN229 and HG7 cells treated with or without NETs. (F) Colony formation assays of LN229 and HG7 cells treated with NETs or NETs combined with DNase I (NETs & DNase I). The statistics are shown in the histogram. (G) Wound-healing assays of LN229 cells treated with or without NETs. (H) Transwell invasion assays of LN229 and HG7 cells treated with NETs or NETs combined with DNase I (NETs & DNase I). The statistics are shown in the histogram. Significant results are presented as * P < 0.05, ** P < 0.01, or *** P < 0.001. Non-significant results are presented as ns.

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    Figure 3

    Neutrophil extracellular traps (NETs) mediate the malignancy of glioma cells via the HMGB1/RAGE/NF-κB axis. (A) Identification of HMGB1 by immunofluorescence assays on NETs. (B) The different RAGE expression in low-grade gliomas and high-grade gliomas. (C) CCK-8 assay of gliomas treated with NETs or NETs combined with FPS-ZM1 (FPS-ZM1 & NETs). (D) Immunofluorescence assays of HMGB1 and RAGE in glioma cells treated with NETs or recombinant HMGB1. (E) Expression of p-ERK1/2, t-ERK1/2 and p-IκB in glioma cells treated with recombinant HMGB1 for different time periods. (F) Expression of p-ERK1/2, t-ERK1/2, and p-IκB in glioma cells treated with NETs, recombinant HMGB1 or FPS-ZM1. (G) Nuclear translocation of NF-κB in LN229 and HG7 cells treated with NETs or NETs combined with FPS-ZM1 (FPS-ZM1 & NETs). Significant results are presented as *** P < 0.001.

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    Figure 4

    The IL-8 secretion of glioma cells is promoted via the HMGB1/RAGE/NF-κB axis. (A) IL-8 expression in different types of gliomas in the TCGA RNA-seq dataset. (B) Kaplan–Meier survival curve of TCGA glioma patients with low or high expression of IL-8. (C) Immunohistochemistry (IHC) assays of IL-8 in patients with low-grade or high-grade gliomas. (D) IHC score of IL-8 in low-grade or high-grade gliomas. (E) IL-8 secretion detected with ELISA in glioma cells treated with neutrophils or NETs. (F) The RNA level of IL-8 in LN229 cells treated with NETs, recombinant HMGB1, FPS-ZM1, U0126, or JSH-23. (G) IL-8 secretion detected with ELISA in glioma cells treated with or without FPS-ZM1, U0126, or JSH-23, followed by recombinant HMGB1 treatment (&FPS-ZM1, &U0126, or &JSH-23). Significant results are presented as *** P < 0.001, or ### P < 0.001. Non-significant results are presented as ns.

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    Figure 5

    IL-8 recruits neutrophils and mediates neutrophil extracellular traps (NETs) formation. (A) Recruitment of neutrophils detected with chemotaxis assays with NETs-primed conditioned medium (CM), CM combined with anti-IL-8 antibody (CM & anti-IL-8), or CM combined with isotype IgG (CM & IgG). (B) Recruitment of neutrophils, detected with chemotaxis assays with different concentrations of IL-8. (C) Expression levels of CXCR2 in different cell lines. (D) Binding affinity of IL-8 and CXCR2 on neutrophils, detected with immunofluorescence assays. (E) Expression of p-PI3K and t-PI3K in neutrophils treated with IL-8 or IL-8 combined with SB225002 (200 nM, CXCR2 inhibitor, Calbiochem). (F) Expression of p-AKT and t-AKT in neutrophils treated with IL-8, SB225002, or LY294002 (5 µM, PI3K inhibitor, EMD, Billerica, MA). (G) ROS activity in neutrophils treated with CM, IL-8, IL-8 combined with SB225002 (SB225002 & IL-8), IL-8 combined with LY294002 (LY294002 & IL-8), IL-8 combined with AKT inhibitor 1/2 (Akt inh. & IL-8; Akt inh., 10 μM, Calbiochem, San Diego, CA), IL-8 combined with DPI (DPI & IL-8; 10 μM, NADPH oxidase inhibitor, Sigma, Saint Louis, MO, USA), or PMA (30 nM). (H) Detection of NETs formation by immunofluorescence in neutrophils treated with CM, IL-8, IL-8 combined with SB225002 (SB225002 & IL-8), IL-8 combined with LY294002 (LY294002 & IL-8), IL-8 combined with AKT inhibitor 1/2 (Akt inh. & IL-8), IL-8 combined with DPI (DPI & IL-8), or PMA. Significant results are presented as *** P < 0.01. Non-significant results are presented as ns.

  • Figure 6
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    Figure 6

    NETs play a role in the crosstalk between glioma progression and tumor microenvironment by regulating the HMGB1/RAGE/IL-8 axis is shown.

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Cancer Biology and Medicine: 17 (1)
Cancer Biology & Medicine
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15 Feb 2020
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Neutrophil extracellular traps mediate the crosstalk between glioma progression and the tumor microenvironment via the HMGB1/RAGE/IL-8 axis
Caijun Zha, Xiangqi Meng, Lulu Li, Shan Mi, Da Qian, Ziwei Li, Pengfei Wu, Shaoshan Hu, Shihong Zhao, Jinquan Cai, Yanhong Liu
Cancer Biology & Medicine Feb 2020, 17 (1) 154-168; DOI: 10.20892/j.issn.2095-3941.2019.0353

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Neutrophil extracellular traps mediate the crosstalk between glioma progression and the tumor microenvironment via the HMGB1/RAGE/IL-8 axis
Caijun Zha, Xiangqi Meng, Lulu Li, Shan Mi, Da Qian, Ziwei Li, Pengfei Wu, Shaoshan Hu, Shihong Zhao, Jinquan Cai, Yanhong Liu
Cancer Biology & Medicine Feb 2020, 17 (1) 154-168; DOI: 10.20892/j.issn.2095-3941.2019.0353
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Subjects

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  • Brain Tumor

Keywords

  • Neutrophil extracellular traps
  • HMGB1
  • IL-8
  • NF-κB
  • glioma microenvironment

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