Advertisement

Acta Neuropathologica

, Volume 110, Issue 3, pp 239–246 | Cite as

Human glioblastomas overexpress ADAMTS-5 that degrades brevican

  • Mitsutoshi Nakada
  • Hisashi Miyamori
  • Daisuke Kita
  • Tomoya Takahashi
  • Junkoh Yamashita
  • Hiroshi Sato
  • Ryu Miura
  • Yu Yamaguchi
  • Yasunori Okada
Regular Paper

Abstract

Selective cleavage of the Glu395-Ser396 bond of brevican, one of the major proteoglycans in adult brain tissues, is thought to be important for glioma cell invasion. Our previous biochemical study demonstrated that ADAMTS-4, a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, has such an activity. In the present study, we examined brevican-degrading activities of ADAMTS-1, -4 and -5 at the cellular level, and their expression and localization in human glioma tissues. In 293T transfectants expressing ADAMTS-4 or ADAMTS-5, brevican was cleaved into two major fragments in an identical pattern, but no such degradation was observed with ADAMTS-1 transfectants. When the expression levels of these ADAMTS species were examined by real-time quantitative PCR, only ADAMTS-5 was found to be overexpressed in glioblastoma tissues compared to control normal brain tissues (P <0.05). In situ hybridization and immunohistochemistry demonstrated that ADAMTS-5 is expressed predominantly in glioblastoma cells. Forced expression of ADAMTS-5 in glioma cell lines stimulated cell invasion. These results demonstrate for the first time that ADAMTS-5 is capable of degrading brevican and is overexpressed in glioblastoma cells, and suggest that ADAMTS-5 may play a role in glioma cell invasion through the cleavage of brevican.

Keywords

ADAMTS Glioma Invasion Brevican Digestion 

Notes

Acknowledgements

We are grateful for the following grant support: Grants-in-aid for young scientists (B-14770707 to M. Nakada) and for scientific research (B2–13470290 to J. Yamashita, B2-14370053 to H. Sato, and B2–11240206 to Y. Okada) from the Ministry of Education, Science and Culture of Japan, and NIH R01 (NS041332 to Y. Yamaguchi).

References

  1. 1.
    Abbaszade I, Liu RQ, Yang F, Rosenfeld SA, Ross OH, Link JR, Ellis DM, Tortorella MD, Pratta MA, Hollis JM, et al (1999) Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. J Biol Chem 274:23443–23450PubMedGoogle Scholar
  2. 2.
    Gary SC, Zerillo CA, Chiang VL, Gaw JU, Gray G, Hockfield S (2000) cDNA cloning, chromosomal localization, and expression analysis of human BEHAB/brevican, a brain specific proteoglycan regulated during cortical development and in glioma. Gene 256:139–147PubMedGoogle Scholar
  3. 3.
    Jaworski DM, Kelly GM, Piepmeier JM, Hockfield S (1996) BEHAB (brain enriched hyaluronan binding) is expressed in surgical samples of glioma and in intracranial grafts of invasive glioma cell lines. Cancer Res 56:2293–2298PubMedGoogle Scholar
  4. 4.
    Kleihues P, Cavenee WK (eds) (2000) World Health Organization classification of tumours. Pathology and genetics of tumours of the nervous system. IARC Press, LyonGoogle Scholar
  5. 5.
    Kuno K, Matsushima K (1998) ADAMTS-1 protein anchors at the extracellular matrix through the thrombospondin type I motifs and its spacing region. J Biol Chem 273:13912–13917PubMedGoogle Scholar
  6. 6.
    Kuno K, Okada Y, Kawashima H, Nakamura H, Miyasaka M, Ohno H, Matsushima K (2000) ADAMTS-1 cleaves a cartilage proteoglycan, aggrecan. FEBS Lett 478:241–245PubMedGoogle Scholar
  7. 7.
    Matthews RT, Gary SC, Zerillo C, Pratta M, Solomon K, Arner EC, Hockfield S (2000) Brain-enriched hyaluronan binding (BEHAB)/brevican cleavage in a glioma cell line is mediated by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family member. J Biol Chem 275:22695–22703PubMedGoogle Scholar
  8. 8.
    Miura R, Aspberg A, Ethell IM, Hagihara K, Schnaar RL, Ruoslahti E, Yamaguchi Y (1999) The proteoglycan lectin domain binds sulfated cell surface glycolipids and promotes cell adhesion. J Biol Chem 274:11431–11438PubMedGoogle Scholar
  9. 9.
    Nakada M, Yamada A, Takino T, Miyamori H, Takahashi T, Yamashita J, Sato H (2001) Suppression of membrane-type 1 matrix metalloproteinase (MMP)-mediated MMP-2 activation and tumor invasion by testican 3 and its splicing variant gene product, N-Tes. Cancer Res 61:8896–8902PubMedGoogle Scholar
  10. 10.
    Nakada M, Miyamori H, Yamashita J, Sato H (2003) Testican 2 abrogates inhibition of membrane-type matrix metalloproteinases by other testican family proteins. Cancer Res 63:3364–3369PubMedGoogle Scholar
  11. 11.
    Nakada M, Niska JA, Miyamori H, McDonough WS, Wu J, Sato H, Berens ME (2004) The phosphorylation of EphB2 receptor regulates migration and invasion of human glioma cells. Cancer Res 64:3179–3185PubMedGoogle Scholar
  12. 12.
    Nakamura H, Fujii Y, Inoki I, Sugimoto K, Tanzawa K, Matsuki H, Miura R, Yamaguchi Y, Okada Y (2000) Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites. J Biol Chem 275:38885–38890PubMedGoogle Scholar
  13. 13.
    Tortorella MD, Burn TC, Pratta MA, Abbaszade I, Hollis JM, Liu R, Rosenfeld SA, Copeland RA, Decicco CP, Wynn R, et al (1999) Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. Science 284:1664–1666PubMedGoogle Scholar
  14. 14.
    Tortorella MD, Liu RQ, Burn T, Newton RC, Arner E (2002) Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4). Matrix Biol 21:499–511PubMedGoogle Scholar
  15. 15.
    Yamada H, Watanabe K, Shimonaka M, Yamaguchi Y (1994) Molecular cloning of brevican, a novel brain proteoglycan of the aggrecan/versican family. J Biol Chem 269:10119–10126PubMedGoogle Scholar
  16. 16.
    Yamaguchi Y (2000) Lecticans: organizers of the brain extracellular matrix. Cell Mol Life Sci 57:276–289PubMedGoogle Scholar
  17. 17.
    Zhang H, Kelly G, Zerillo C, Jaworski DM, Hockfield S (1998) Expression of a cleaved brain-specific extracellular matrix protein mediates glioma cell invasion in vivo. J Neurosci 18:2370–2376PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Mitsutoshi Nakada
    • 1
    • 2
  • Hisashi Miyamori
    • 2
  • Daisuke Kita
    • 1
  • Tomoya Takahashi
    • 1
  • Junkoh Yamashita
    • 1
  • Hiroshi Sato
    • 2
  • Ryu Miura
    • 3
  • Yu Yamaguchi
    • 3
  • Yasunori Okada
    • 4
  1. 1.Department of Neurosurgery, Division of Neuroscience, Graduate School of Medical ScienceKanazawa UniversityIshikawaJapan
  2. 2.Department of Molecular Virology and Oncology, Cancer Research InstituteKanazawa UniversityIshikawaJapan
  3. 3.The Burnham InstituteLa JollaUSA
  4. 4.Department of Pathology, School of MedicineKeio UniversityTokyoJapan

Personalised recommendations