Ionizing radiation is widely used for patient with glioblastoma (GBM). However, the effect of radiation on patient survival is marginal and upon recurrence tumors frequently shift toward mesenchymal subtype adopting invasiveness. Here, we show that ionizing radiation affects biomechanical tension in GBM microenvironment and provides proinvasive extracellular signaling cue, hyaluronic acid (HA)-rich condition. In response to radiation, HA production was increased in GBM cells by HA synthase-2 (HAS2) that was transcriptionally upregulated by NF-ĸB. Notably, NF-ĸB was persistently activated by IL-1α-feedback loop, making HA abundance in tumor microenvironment after radiation. Radiation-induced HA abundance causally has been linked to invasiveness of GBM cells by generating movement track as an extracellular matrix, and by acting as a signaling ligand for CD44 receptor, leading to SRC activation, which is sufficient for mesenchymal shift of GBM cells. Collectively, our findings provide an explanation for the frequent brain tumor relapse after radiotherapy, and potential therapeutic targets to block mesenchymal shift upon relapse.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 2012;26:756–84.

  2. 2.

    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.

  3. 3.

    Dirks PB. Brain tumor stem cells: bringing order to the chaos of brain cancer. J Clin Oncol. 2008;26:2916–24.

  4. 4.

    Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao JH, et al. Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell. 2011;19:640–51.

  5. 5.

    Catton C, Milosevic M, Warde P, Bayley A, Crook J, Bristow R, et al. Recurrent prostate cancer following external beam radiotherapy: follow-up strategies and management. Urol Clin North Am. 2003;30:751–63.

  6. 6.

    Kim MJ, Kim RK, Yoon CH, An S, Hwang SG, Suh Y, et al. Importance of PKCdelta signaling in fractionated-radiation-induced expansion of glioma-initiating cells and resistance to cancer treatment. J Cell Sci. 2011;124:3084–94.

  7. 7.

    Kim YH, Yoo KC, Cui YH, Uddin N, Lim EJ, Kim MJ, et al. Radiation promotes malignant progression of glioma cells through HIF-1alpha stabilization. Cancer Lett. 2014;354:132–41.

  8. 8.

    Shankar A, Kumar S, Iskander AS, Varma NR, Janic B, deCarvalho A, et al. Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo. Chin J Cancer. 2014;33:148–58.

  9. 9.

    Gladson CL. The extracellular matrix of gliomas: modulation of cell function. J Neuropathol Exp Neurol. 1999;58:1029–40.

  10. 10.

    Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG. Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol. 2004;36:1046–69.

  11. 11.

    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.

  12. 12.

    Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157–73.

  13. 13.

    Freije WA, Castro-Vargas FE, Fang Z, Horvath S, Cloughesy T, Liau LM, et al. Gene expression profiling of gliomas strongly predicts survival. Cancer Res. 2004;64:6503–10.

  14. 14.

    Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature. 2010;463:318–25.

  15. 15.

    Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, et al. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci USA. 2013;110:8644–9.

  16. 16.

    Hyc A, Osiecka-Iwan A, Niderla-Bielinska J, Jankowska-Steifer E, Moskalewski S. Pro- and anti-inflammatory cytokines increase hyaluronan production by rat synovial membrane in vitro. Int J Mol Med. 2009;24:579–85.

  17. 17.

    Vigetti D, Genasetti A, Karousou E, Viola M, Moretto P, Clerici M, et al. Proinflammatory cytokines induce hyaluronan synthesis and monocyte adhesion in human endothelial cells through hyaluronan synthase 2 (HAS2) and the nuclear factor-kappaB (NF-kappaB) pathway. J Biol Chem. 2010;285:24639–45.

  18. 18.

    Yoshida Y, Kumar A, Koyama Y, Peng H, Arman A, Boch JA, et al. Interleukin 1 activates STAT3/nuclear factor-kappaB cross-talk via a unique TRAF6- and p65-dependent mechanism. J Biol Chem. 2004;279:1768–76.

  19. 19.

    Tammi RH, Passi AG, Rilla K, Karousou E, Vigetti D, Makkonen K, et al. Transcriptional and post-translational regulation of hyaluronan synthesis. FEBS J. 2011;278:1419–28.

  20. 20.

    Bohrer LR, Chuntova P, Bade LK, Beadnell TC, Leon RP, Brady NJ, et al. Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation. Cancer Res. 2014;74:374–86.

  21. 21.

    Entwistle J, Hall CL, Turley EA. HA receptors: regulators of signalling to the cytoskeleton. J Cell Biochem. 1996;61:569–77.

  22. 22.

    Bourguignon LY, Zhu H, Shao L, Chen YW. CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration. J Biol Chem. 2001;276:7327–36.

  23. 23.

    Colman H, Zhang L, Sulman EP, McDonald JM, Shooshtari NL, Rivera A, et al. A multigene predictor of outcome in glioblastoma. Neuro Oncol. 2010;12:49–57.

  24. 24.

    Joseph JV, Conroy S, Pavlov K, Sontakke P, Tomar T, Eggens-Meijer E, et al. Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1alpha-ZEB1 axis. Cancer Lett. 2015;359:107–16.

  25. 25.

    Du J, Bernasconi P, Clauser KR, Mani DR, Finn SP, Beroukhim R, et al. Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy. Nat Biotechnol. 2009;27:77–83.

  26. 26.

    de Groot J, Milano V. Improving the prognosis for patients with glioblastoma: the rationale for targeting Src. J Neurooncol. 2009;95:151–63.

  27. 27.

    Sun Z, Andersson R. NF-kappaB activation and inhibition: a review. Shock. 2002;18:99–106.

  28. 28.

    Hartupee J, Li X, Hamilton T. Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1. J Biol Chem. 2008;283:15689–93.

  29. 29.

    Saavalainen K, Tammi MI, Bowen T, Schmitz ML, Carlberg C. Integration of the activation of the human hyaluronan synthase 2 gene promoter by common cofactors of the transcription factors retinoic acid receptor and nuclear factor kappaB. J Biol Chem. 2007;282:11530–9.

  30. 30.

    Bhat KP, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, et al. Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma. Cancer Cell. 2013;24:331–46.

  31. 31.

    Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene. 2009;28:3949–59.

  32. 32.

    Hwang E, Yoo KC, Kang SG, Kim RK, Cui YH, Lee HJ, et al. PKCdelta activated by c-MET enhances infiltration of human glioblastoma cells through NOTCH2 signaling. Oncotarget. 2016;7:4890–902.

  33. 33.

    Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.

  34. 34.

    Kim YG, Jeon S, Sin GY, Shim JK, Kim BK, Shin HJ, et al. Existence of glioma stroma mesenchymal stemlike cells in Korean glioma specimens. Child’s Nerv Syst. 2013;29:549–63.

  35. 35.

    Lal S, Lacroix M, Tofilon P, Fuller GN, Sawaya R, Lang FF. An implantable guide-screw system for brain tumor studies in small animals. J Neurosurg. 2000;92:326–33.

  36. 36.

    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

Download references


We thank Akio Soeda (Department of Neurological Surgery, Gifu University, Japan) for providing patient-derived X01 GBM cells and Incheol Shin (Department of Life Science, Hanyang University, Korea) for vectors pBMN and pBMN-CD44.


This work was supported by the National Research Foundation (NRF) and Ministry of Science, ICT and Future Planning, Korean Government, through its National Nuclear Technology Program (NRF-2015M2A2A7A01044998 and NRF-2016R1E1A1A01942075).

Author information

Author notes

  1. These authors contributed equally: Ki-Chun Yoo, Yongjoon Suh


  1. Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Korea

    • Ki-Chun Yoo
    • , Yongjoon Suh
    • , Yoojeong An
    • , Nizam Uddin
    • , Yan-Hong Cui
    •  & Su-Jae Lee
  2. Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea

    • Hae-June Lee
    •  & Ye Ji Jeong
  3. Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Korea

    • Tae-Hoon Roh
    • , Jin-Kyoung Shim
    • , Jong Hee Chang
    •  & Seok-Gu Kang
  4. Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, 10408, Korea

    • Jong Bae Park
  5. Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea

    • Min-Jung Kim
  6. Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, 34057, Korea

    • In-Gyu Kim


  1. Search for Ki-Chun Yoo in:

  2. Search for Yongjoon Suh in:

  3. Search for Yoojeong An in:

  4. Search for Hae-June Lee in:

  5. Search for Ye Ji Jeong in:

  6. Search for Nizam Uddin in:

  7. Search for Yan-Hong Cui in:

  8. Search for Tae-Hoon Roh in:

  9. Search for Jin-Kyoung Shim in:

  10. Search for Jong Hee Chang in:

  11. Search for Jong Bae Park in:

  12. Search for Min-Jung Kim in:

  13. Search for In-Gyu Kim in:

  14. Search for Seok-Gu Kang in:

  15. Search for Su-Jae Lee in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Seok-Gu Kang or Su-Jae Lee.

Electronic supplementary material

About this article

Publication history





Issue Date