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Newly generated heparanase knock-out mice unravel co-regulation of heparanase and matrix metalloproteinases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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2009 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 4, e5181- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Heparanase, a mammalian endo-beta-D-glucuronidase, specifically degrades heparan sulfate proteoglycans ubiquitously associated with the cell surface and extracellular matrix. This single gene encoded enzyme is over-expressed in most human cancers, promoting tumor metastasis and angiogenesis. PRINCIPAL FINDINGS: We report that targeted disruption of the murine heparanase gene eliminated heparanase enzymatic activity, resulting in accumulation of long heparan sulfate chains. Unexpectedly, the heparanase knockout (Hpse-KO) mice were fertile, exhibited a normal life span and did not show prominent pathological alterations. The lack of major abnormalities is attributed to a marked elevation in the expression of matrix metalloproteinases, for example, MMP2 and MMP14 in the Hpse-KO liver and kidney. Co-regulation of heparanase and MMPs was also noted by a marked decrease in MMP (primarily MMP-2,-9 and 14) expression following transfection and over-expression of the heparanase gene in cultured human mammary carcinoma (MDA-MB-231) cells. Immunostaining (kidney tissue) and chromatin immunoprecipitation (ChIP) analysis (Hpse-KO mouse embryonic fibroblasts) suggest that the newly discovered co-regulation of heparanase and MMPs is mediated by stabilization and transcriptional activity of beta-catenin. CONCLUSIONS/SIGNIFICANCE: The lack of heparanase expression and activity was accompanied by alterations in the expression level of MMP family members, primarily MMP-2 and MMP-14. It is conceivable that MMP-2 and MMP-14, which exert some of the effects elicited by heparanase (i.e., over branching of mammary glands, enhanced angiogenic response) can compensate for its absence, in spite of their different enzymatic substrate. Generation of viable Hpse-KO mice lacking significant abnormalities may provide a promising indication for the use of heparanase as a target for drug development.

Place, publisher, year, edition, pages
2009. Vol. 4, no 4, e5181- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-103526DOI: 10.1371/journal.pone.0005181ISI: 000265506100004PubMedID: 19360105OAI: oai:DiVA.org:uu-103526DiVA: diva2:218390
Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2011-06-28Bibliographically approved
In thesis
1. Structure and functions of heparan sulfate/heparin – Importance of glucuronyl C5-epimerase and heparanase
Open this publication in new window or tab >>Structure and functions of heparan sulfate/heparin – Importance of glucuronyl C5-epimerase and heparanase
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate (HS) and heparin are linear polysaccharide chains covalently O-linked to serine residues within the core proteins, so called HS proteoglycans (PGs) or heparin PG. HSPGs are produced by almost all mammalian cells and known to play important roles in developmental processes, physiological and pathological conditions; whereas heparin PG is produced by mast cells and best known as an anticoagulant in clinic.

Biosynthesis of HS/heparin occurs in Golgi compartment and involves many enzymes, one of which is glucuronyl C5-epimerase (Hsepi) that catalyzes the conversion of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA). Heparanase is an enzyme involved in metabolism of HS; it cleaves the linkage between GlcA and glucosamine residues in HS/heparin chains. Heparanase is expressed essentially by all cells and found up-regulated in many metastatic tumors.

This thesis focuses on the structure and functions of HS/heparin through studies on the implications of Hsepi and heparanase. My study demonstrated that the modification catalyzed by Hsepi is critical for HS-dependent function of growth factors, especially FGF2; heparanase is involved in regulation of HS biosynthesis and matrix metalloproteinases expression; moreover, my experimental data demonstrated the functions of heparin in mast cells, showing cleavage of heparin by heparanase contributes to modulation of protease storage in mast cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 46 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 470
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
urn:nbn:se:uu:diva-107202 (URN)978-91-554-7571-0 (ISBN)
Public defence
2009-09-11, C10:301, BMC, Husargatan 3, Uppsala, 09:00 (English)
Available from: 2009-08-20 Created: 2009-07-28 Last updated: 2009-08-20Bibliographically approved

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Li, Jin-Ping
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