Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma.

Abstract

The heparan sulfate (HS) proteoglycan, syndecan-1, plays a major role in multiple myeloma (MM) by concentrating heparin-binding growth factors on the surface of MM cells (MMCs). Using Affymetrix microarrays and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), we show that the gene encoding heparanase (HPSE), an enzyme that cleaves HS chains, is expressed by 11 of 19 myeloma cell lines (HMCLs). In HSPE(pos) HMCLs, syndecan-1 gene expression and production of soluble syndecan-1, unlike expression of membrane syndecan-1, were significantly increased. Knockdown of HPSE by siRNA resulted in a decrease of syndecan-1 gene expression and soluble syndecan-1 production without affecting membrane syndecan-1 expression. Thus, HPSE influences expression and shedding of syndecan-1. Contrary to HMCLs, HPSE is expressed in only 4 of 39 primary MMC samples, whereas it is expressed in 36 of 39 bone marrow (BM) microenvironment samples. In the latter, HPSE is expressed at a median level in polymorphonuclear cells and T cells; it is highly expressed in monocytes and osteoclasts. Affymetrix data were validated at the protein level, both on HMCLs and patient samples. We report for the first time that a gene's expression mainly in the BM environment (ie, HSPE) is associated with a shorter event-free survival of patients with newly diagnosed myeloma treated with high-dose chemotherapy and stem cell transplantation. Our study suggests that clinical inhibitors of HPSE could be beneficial for patients with MM.

• Authors: Karène Mahtouk, Dirk Hose, Pierre Raynaud, Michael Hundemer, Michel Jourdan, Eric Jourdan, Veronique Pantesco, Marion Baudard, John De Vos, Marion Larroque, Thomas Moehler, Jean-Francois Rossi, Thierry Rème, Hartmut Goldschmidt, Bernard Klein
• Journal: Blood (Blood) Vol. 109 Issue 11 Pg. 4914-23 (Jun 01 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17339423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Syndecan-1
• heparanase
• Glucuronidase

Topics

• Aged
• Bone Marrow (metabolism)
• Bone Marrow Cells (metabolism)
• Cell Line, Tumor
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Glucuronidase (physiology)
• Humans
• Middle Aged
• Monocytes (metabolism)
• Multiple Myeloma (diagnosis, enzymology, pathology)
• Neutrophils (metabolism)
• Osteoclasts (metabolism)
• Prognosis
• Syndecan-1 (biosynthesis)