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Heparanase promotes glioma progression via enhancing CD24 expression
Rappaport Fac Med, TICC, Haifa, Israel.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
Shantou Univ, Med Coll, Shantou, Peoples R China.
Rambam Hlth Care Campus, Dept Pathol, Haifa, Israel.
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 6, p. 1596-1608Article in journal (Refereed) Published
Abstract [en]

Heparanase is an endo-beta-d-glucuronidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans. Compelling evidence tie heparanase levels with all steps of tumor formation including tumor initiation, growth, metastasis and chemo-resistance, likely involving augmentation of signaling pathways and gene transcription. In order to reveal the molecular mechanism(s) underlying the protumorigenic properties of heparanase, we established an inducible (Tet-on) system in U87 human glioma cells and applied gene array methodology in order to identify genes associated with heparanase induction. We found that CD24, a mucin-like cell adhesion protein, is consistently upregulated by heparanase and by heparanase splice variant devoid of enzymatic activity, whereas heparanase gene silencing was associated with decreased CD24 expression. This finding was further substantiated by a similar pattern of heparanase and CD24 immunostaining in glioma patients (Pearson's correlation; R = 0.66, p = 0.00001). Noteworthy, overexpression of CD24 stimulated glioma cell migration, invasion, colony formation in soft agar and tumor growth in mice suggesting that CD24 functions promote tumor growth. Likewise, anti-CD24 neutralizing monoclonal antibody attenuated glioma tumor growth, and a similar inhibition was observed in mice treated with a neutralizing mAb directed against L1 cell adhesion molecule (L1CAM), a ligand for CD24. Importantly, significant shorter patient survival was found in heparanase-high/CD24-high tumors vs. heparanase-high/CD24-low tumors for both high-grade and low-grade glioma (p = 0.02). Our results thus uncover a novel heparanase-CD24-L1CAM axis that plays a significant role in glioma tumorigenesis.

Place, publisher, year, edition, pages
WILEY , 2019. Vol. 145, no 6, p. 1596-1608
Keywords [en]
heparanase, glioma, CD24, L1CAM
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-392121DOI: 10.1002/ijc.32375ISI: 000476557000015PubMedID: 31032901OAI: oai:DiVA.org:uu-392121DiVA, id: diva2:1348208
Available from: 2019-09-03 Created: 2019-09-03 Last updated: 2019-09-03Bibliographically approved

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Spyrou, ArgyrisForsberg Nilsson, Karin

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