Journal of Molecular Medicine

, Volume 94, Issue 8, pp 867–874 | Cite as

Pivotal role of high-mobility group box 1 (HMGB1) signaling pathways in glioma development and progression

  • Efthalia Angelopoulou
  • Christina Piperi
  • Christos Adamopoulos
  • Athanasios G. Papavassiliou
Review

Abstract

Human gliomas represent the most common type of intracranial tumors, with highest morbidity and mortality. They are characterized by excessive invasiveness and cell proliferation while their unclear boundaries predispose to tumor recurrence soon after conventional treatment. Elucidation of the molecular mechanisms implicated in their development and/or treatment resistance is highly demanded. The high-mobility group box 1 (HMGB1) protein, a highly conserved nuclear protein that functions as a chromatin-binding factor, facilitating nucleosome stabilization and regulating gene transcription, has been implicated in glioma formation and progression. Extracellular released HMGB1 binds to high-affinity receptors, including the receptor for advanced glycation end-products (RAGE) and toll-like receptor (TLR)-2, TLR-4, and TLR-9. Upon receptor binding, HMGB1 triggers the activation of key signaling pathways and immune responses, involved in the regulation of cell growth, differentiation, motility, and apoptosis. Based on the type of receptor and/or cell, HMGB1 is capable to promote oncogenesis or suppress tumor growth, thus affecting treatment efficacy. Herein, we discuss recent evidence implicating HMGB1 in glioma cell differentiation, proliferation, and metastasis with both clinical and prognostic significance. In addition, potential therapeutic approaches to target this protein in order to reduce chemoresistance of glioma cells are also addressed.

Keywords

HMGB1 Gliomas Brain tumors RAGE TLRs Immunotherapy 

Notes

Acknowledgments

E. Angelopoulou is supported by a scholarship from “Alexander S. Onassis Public Benefit Foundation,” Greece.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Zhang J, Liu C, Hou R (2014) Knockdown of HMGB1 improves apoptosis and suppresses proliferation and invasion of glioma cells. Chin J Cancer Res 26:658–668PubMedPubMedCentralGoogle Scholar
  2. 2.
    Ostrom QT, Bauchet L, Davis FG et al (2014) The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol 16:896–913CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Stupp R, Brada M, den Bent MJ V, Tonn JC, Pentheroudakis G, Group EGW (2014) High-grade glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(Suppl 3):iii93–101CrossRefPubMedGoogle Scholar
  4. 4.
    Wang XJ, Zhou SL, Fu XD, Zhang YY, Liang B, Shou JX, Wang JY, Ma J (2015) Clinical and prognostic significance of high-mobility group box-1 in human gliomas. Exp Ther Med 9:513–518PubMedGoogle Scholar
  5. 5.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Alifieris C, Trafalis DT (2015) Glioblastoma multiforme: pathogenesis and treatment. Pharmacol Ther 152:63–82CrossRefPubMedGoogle Scholar
  7. 7.
    Prados MD, Levin V (2000) Biology and treatment of malignant glioma. Semin Oncol 27(3 Suppl 6):1–10PubMedGoogle Scholar
  8. 8.
    Candolfi M, Yagiz K, Foulad D et al (2009) Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity. Clin Cancer Res 15:4401–4414CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kjellman C, Olofsson SP, Hansson O, Von Schantz T, Lindvall M, Nilsson I, Salford LG, Sjogren HO, Widegren B (2000) Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma. Int J Cancer 89:251–258CrossRefPubMedGoogle Scholar
  10. 10.
    Bassi R, Giussani P, Anelli V, Colleoni T, Pedrazzi M, Patrone M, Viani P, Sparatore B, Melloni E, Riboni L (2008) HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration. J Neurooncol 87:23–33CrossRefPubMedGoogle Scholar
  11. 11.
    Molina JR, Hayashi Y, Stephens C, Georgescu MM (2010) Invasive glioblastoma cells acquire stemness andincreased Akt activation. Neoplasia 12:453–463CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Argyriou AA, Antonacopoulou A, Iconomou G, Kalofonos HP (2009) Treatment options for malignant gliomas, emphasizing towards new molecularly targeted therapies. Crit Rev Oncol Hematol 69:199–210CrossRefPubMedGoogle Scholar
  13. 13.
    Curtin JF, Liu N, Candolfi M et al (2009) HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med 6, e10. doi: 10.1371/journal.pmed.1000010 CrossRefPubMedGoogle Scholar
  14. 14.
    Zhao WP, Chen QX (2015) Effects of HMGB1 on proliferation and apoptosis of human brain glioma CD133 cells. Bratisl Med J 116:480–485CrossRefGoogle Scholar
  15. 15.
    Yanai H, Matsuda A, An J et al (2013) Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection. Proc Natl Acad Sci U S A 110:20699–20704CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wild CA, Brandau S, Lotfi R, Mattheis S, Gu X, Lang S, Bergmann C (2012) HMGB1 is overexpressed in tumor cells and promotes activity of regulatory T cells in patients with head and neck cancer. Oral Oncol 48:409–416CrossRefPubMedGoogle Scholar
  17. 17.
    Goodwin GH, Johns EW (1973) Isolation and characterisation of two calf-thymus chromatin non-histone proteins with high contents of acidic and basic amino acids. Eur J Biochem 40:215–219CrossRefPubMedGoogle Scholar
  18. 18.
    Kang R, Chen R, Zhang Q et al (2014) HMGB1 in health and disease. Mol Aspects Med 40:1–116CrossRefPubMedGoogle Scholar
  19. 19.
    Calogero S, Grassi F, Aguzzi A, Voigtlander T, Ferrier P, Ferrari S, Bianchi ME (1999) The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat Genet 22:276–280CrossRefPubMedGoogle Scholar
  20. 20.
    Tang D, Kang R, Van Houten B, Zeh HJ, Billiar TR, Lotze MT (2014) High mobility group box 1 (HMGB1) phenotypic role revealed with stress. Mol Med 20:359–362CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Muller S, Ronfani L, Bianchi ME (2004) Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function. J Intern Med 255:332–343CrossRefPubMedGoogle Scholar
  22. 22.
    Kang R, Zhang Q, Zeh HJ 3rd, Lotze MT, Tang D (2013) HMGB1 in cancer: good, bad, or both? Clin Cancer Res 19:4046–4057CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Jiao Y, Wang HC, Fan SJ (2007) Growth suppression and radiosensitivity increase by HMGB1 in breast cancer. Acta Pharmacol Sin 28:1957–1967CrossRefPubMedGoogle Scholar
  24. 24.
    Yang H, Wang H, Chavan SS, Andersson U (2015) High mobility group box protein 1 (HMGB1): the prototypical endogenous danger molecule. Mol Med 21(Suppl 1):S6–S12CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Chen M, Liu Y, Varley P, Chang Y, He XX, Huang H, Tang D, Lotze MT, Lin J, Tsung A (2015) High-mobility group box 1 promotes hepatocellular carcinoma progression through miR-21-mediated matrix metalloproteinase activity. Cancer Res 75:1645–1656CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Silveira Correa TC, Massaro RR, Brohem CA, Taboga SR, Lamers ML, Santos MF, Maria- Engler SS (2010) RECK-mediated inhibition of glioma migration and invasion. J Cell Biochem 110:52–61PubMedGoogle Scholar
  27. 27.
    Tang Q, Li J, Zhu H, Li P, Zou Z, Xiao Y (2013) Hmgb1-IL-23-IL-17-IL-6-Stat3 axis promotes tumor growth in murine models of melanoma. Mediators Inflamm 2013:713859PubMedPubMedCentralGoogle Scholar
  28. 28.
    Zhu L, Li X, Chen Y, Fang J, Ge Z (2015) High-mobility group box 1: a novel inducer of the epithelial-mesenchymal transition in colorectal carcinoma. Cancer Lett 357:527–534CrossRefPubMedGoogle Scholar
  29. 29.
    Chen RC, Yi PP, Zhou RR, Xiao MF, Huang ZB, Tang DL, Huang Y, Fan XG (2014) The role of HMGB1-RAGE axis in migration and invasion of hepatocellular carcinoma cell lines. Mol Cell Biochem 390:271–280CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lv W, Chen N, Lin Y, Ma H, Ruan Y, Li Z, Li X, Pan X, Tian X (2016) Macrophage migration inhibitory factor promotes breast cancer metastasis via activation of HMGB1/TLR4/NF kappa B axis. Cancer Lett 375:245–255CrossRefPubMedGoogle Scholar
  31. 31.
    Gupta P, Ghosh S, Nagarajan A, Mehta VS, Sen E (2013) beta-defensin-3 negatively regulates TLR4-HMGB1axis mediated HLA-G expression in IL-1beta treated glioma cells. Cell Signal 25:682–689CrossRefPubMedGoogle Scholar
  32. 32.
    Yang Y, Huang JQ, Zhang X, Shen LF (2015) MiR-129-2 functions as a tumor suppressor in glioma cells by targeting HMGB1 and is down-regulated by DNA methylation. Mol Cell Biochem 404:229–239CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Yu X, Song H, Xia T, Han S, Xiao B, Luo L, Xi Y, Guo J (2013) Growth inhibitory effects of three miR-129 family members on gastric cancer. Gene 532:87–93CrossRefPubMedGoogle Scholar
  34. 34.
    Hua S, Xiao L, Wu D (2015) Effect of HMGB1 on proliferation of human nasopharyngeal carcinoma cell line C666-1 in vitro. Nan fang yi ke da xue xue bao 35:1540–1545PubMedGoogle Scholar
  35. 35.
    Karaayvaz M, Zhai H, Ju J (2013) miR-129 promotes apoptosis and enhances chemosensitivity to 5.doi: 10.1038/cddis.2013.193
  36. 36.
    Luo J, Chen J, He L (2015) mir-129-5p attenuates irradiation-induced autophagy and decreases radioresistance of breast cancer cells by targeting HMGB1. Med Sci Monit 21:4122–4129CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Sun KK, Ji C, Li X, Zhang L, Deng J, Zhong N, Wu XY (2013) Overexpression of high mobility group protein B1 correlates with the proliferation and metastasis of lung adenocarcinoma cells. Mol Med Rep 7:1678–1682PubMedGoogle Scholar
  38. 38.
    Zhang J, Kou YB, Zhu JS, Chen WX, Li S (2014) Knockdown of HMGB1 inhibits growth and invasion of gastric cancer cells through the NF-kappaB pathway in vitro and in vivo. Int J Oncol 44:1268–1276PubMedGoogle Scholar
  39. 39.
    Sanson M, Thillet J, Hoang-Xuan K (2004) Molecular changes in gliomas. Curr Opin Oncol 16:607–613CrossRefPubMedGoogle Scholar
  40. 40.
    Gnanasekar M, Thirugnanam S, Ramaswamy K (2009) Short hairpin RNA (shRNA) constructs targeting high mobility group box-1 (HMGB1) expression leads to inhibition of prostate cancer cell survival and apoptosis. Int J Oncol 34:425–431PubMedGoogle Scholar
  41. 41.
    Meng Q, Zhao J, Liu H, Zhou G, Zhang W, Xu X, Zheng M (2014) HMGB1 promotes cellular proliferation and invasion, suppresses cellular apoptosis in osteosarcoma. Tumour Biol 35:12265–12274CrossRefPubMedGoogle Scholar
  42. 42.
    Kang R, Tang D, Schapiro NE, Livesey KM, Farkas A, Loughran P, Bierhaus A, Lotze MT, Zeh HJ (2010) Thereceptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promotingpancreatic tumor cell survival. Cell Death Differ 17:666–676CrossRefPubMedGoogle Scholar
  43. 43.
    Chung HW, Lee SG, Kim H, Hong DJ, Chung JB, Stroncek D, Lim JB (2009) Serum high mobility group box-1 (HMGB1) is closely associated with the clinical and pathologic features of gastric cancer. J Transl Med 7:38CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hudson BI, Kalea AZ, Del Mar AM, Harja E, Boulanger E, D’Agati V, Schmidt AM (2008) Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem 283:34457–34468CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Salhia B, Tran NL, Symons M, Winkles JA, Rutka JT, Berens ME (2006) Molecular pathways triggering glioma cell invasion. Expert Rev Mol Diagn 6:613–626CrossRefPubMedGoogle Scholar
  46. 46.
    Lee YD, Cui MN, Yoon HH, Kim HY, Oh IH, Lee JH (2014) Down-modulation of Bis reduces the invasive ability of glioma cells induced by TPA, through NF-kappaB mediated activation of MMP-9. BMB Rep 47:262–267CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    El-Badrawy MK, Yousef AM, Shaalan D, Elsamanoudy AZ (2014) Matrix metalloproteinase-9 expression in lung cancer patients and its relation to serum MMP-9 activity, pathologic type, and prognosis. J Bronchology Interv Pulmonol 21:327–334CrossRefPubMedGoogle Scholar
  48. 48.
    Ordonez R, Carbajo-Pescador S, Prieto-Dominguez N, Garcia-Palomo A, Gonzalez-Gallego J, Mauriz JL (2014) Inhibition of matrix metalloproteinase-9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells. J Pineal Res 56:20–30CrossRefPubMedGoogle Scholar
  49. 49.
    Deng S, Zhu S, Qiao Y, Liu YJ, Chen W, Zhao G, Chen J (2014) Recent advances in the role of toll-like receptors and TLR agonists in immunotherapy for human glioma. Protein Cell 5:899–911CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Vinnakota K, Hu F, Ku MC et al (2013) Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion. Neuro Oncol 15:1457–1468CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Noch E, Khalili K (2009) Molecular mechanisms of necrosis in glioblastoma: the role of glutamate excitotoxicity. Cancer Biol Ther 8:1791–1797CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Pasi F, Paolini A, Nano R, Di Liberto R, Capelli E (2014) Effects of single or combined treatments with radiation and chemotherapy on survival and danger signals expression in glioblastoma cell lines. Biomed Res Int 2014:453497CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Ibrahim ZA, Armour CL, Phipps S, Sukkar MB (2013) RAGE and TLRs: relatives, friends or neighbours? Mol Immunol 56:739–744CrossRefPubMedGoogle Scholar
  54. 54.
    Wharton SB, McNelis U, Bell HS, Whittle IR (2000) Expression of poly(ADP-ribose) polymerase and distribution of poly(ADP-ribosyl)ation in glioblastoma and in a glioma multicellular tumour spheroid model. Neuropath Appl Neuro 26:528–535CrossRefGoogle Scholar
  55. 55.
    Musumeci D, Roviello GN, Montesarchio D (2014) An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies. Pharmacol Ther 141:347–357CrossRefPubMedGoogle Scholar
  56. 56.
    Arumugam T, Ramachandran V, Gomez SB, Schmidt AM, Logsdon CD (2012) S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis. Clin Cancer Res 18:4356–4364CrossRefPubMedGoogle Scholar
  57. 57.
    Taguchi A, Blood DC, del Toro G et al (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405:354–360CrossRefPubMedGoogle Scholar
  58. 58.
    Shin JH, Kim ID, Kim SW et al (2014) Ethyl pyruvate inhibits HMGB1 phosphorylation and release by chelating calcium. Mol Med 20:649–657Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Efthalia Angelopoulou
    • 1
  • Christina Piperi
    • 1
  • Christos Adamopoulos
    • 1
  • Athanasios G. Papavassiliou
    • 1
  1. 1.Department of Biological Chemistry, Medical SchoolNational and Kapodistrian University of AthensAthensGreece

Personalised recommendations