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Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate

Nature Chemical Biology volume 3, pages 773–778 (2007)Cite this article

Abstract

Heparan sulfate proteoglycans (HSPGs) interact with numerous proteins of importance in animal development and homeostasis1,2,3. Heparanase, which is expressed in normal tissues and upregulated in angiogenesis, cancer and inflammation, selectively cleaves β-glucuronidic linkages in HS chains. In a previous study, we transgenically overexpressed heparanase in mice to assess the overall effects of heparanase on HS metabolism. Metabolic labeling confirmed extensive fragmentation of HS in vivo4,5. In the current study we found that in liver showing excessive heparanase overexpression, HSPG turnover is accelerated along with upregulation of HS N- and O-sulfation, thus yielding heparin-like chains without the domain structure typical of HS. Heparanase overexpression in other mouse organs and in human tumors correlated with increased 6-O-sulfation of HS, whereas the domain structure was conserved. The heavily sulfated HS fragments strongly promoted formation of ternary complexes with fibroblast growth factor 1 (FGF1) or FGF2 and FGF receptor 1. Heparanase thus contributes to regulation of HS biosynthesis in a way that may promote growth factor action in tumor angiogenesis and metastasis.

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Figure 1: Structural analysis of liver HS.
Figure 2: Assessment of liver HSPG turnover.
Figure 3: Localization of heparanase in liver tissue and hepatocytes.
Figure 4: Interactions of HS with FGFs and their receptor.

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Acknowledgements

We thank L. Nylund for expert technical assistance. This work was supported by the Swedish Research Council (32X-15023), the Swedish Cancer Society (4708-B02-01XAA), the Swedish Foundation for Strategic Research (A303:156e), the European Commission (QLK3-CT-2002-02049) and Polysackaridforskning AB (Uppsala, Sweden).

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Author notes

  1. Martha L Escobar Galvis and Juan Jia: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Biochemistry and Microbiology, University of Uppsala, The Biomedical Center, Box 582, Husargatan 3, Uppsala, SE-751 23, Sweden

    Martha L Escobar Galvis, Juan Jia, Nadja Jastrebova, Dorothe Spillmann, Eva Gottfridsson, Ulf Lindahl & Jin-Ping Li

  2. Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, University of Uppsala, Dag Hammarskjölds väg 20, Uppsala, SE-751 85, Sweden

    Xiao Zhang

  3. Department of Biochemistry, 280 Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Geert Grooteplein 28, route 259, Nijmegen, 6500 HB, The Netherlands

    Toin H van Kuppevelt

  4. Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, 1 Efron Street, Technion, 31096, Haifa, Israel

    Eyal Zcharia & Israel Vlodavsky

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Contributions

M.L.E.G., J.J., X.Z., N.J., D.S. and E.G. performed the experiments; T.H.v.K., E.Z. and I.V. provided reagents and specimens; U.L. and J.-P.L. designed experiments and prepared the manuscript.

Corresponding author

Correspondence to Jin-Ping Li.

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Supplementary Figures 1–5, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 2603 kb)

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Escobar Galvis, M., Jia, J., Zhang, X. et al. Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate. Nat Chem Biol 3, 773–778 (2007). https://doi.org/10.1038/nchembio.2007.41

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