title: 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.affiliation: Institute of Research in Biology, Centre Hospitalier Universitaire Montpellier, 99 rue Puech Villa, 34197 Montpellier Cedex 5, France.
authors.forename: Karène
authors.initials: K
authors.lastname: Mahtouk
authors.forename: Dirk
authors.initials: D
authors.lastname: Hose
authors.forename: Pierre
authors.initials: P
authors.lastname: Raynaud
authors.forename: Michael
authors.initials: M
authors.lastname: Hundemer
authors.forename: Michel
authors.initials: M
authors.lastname: Jourdan
authors.forename: Eric
authors.initials: E
authors.lastname: Jourdan
authors.forename: Veronique
authors.initials: V
authors.lastname: Pantesco
authors.forename: Marion
authors.initials: M
authors.lastname: Baudard
authors.forename: John
authors.initials: J
authors.lastname: De Vos
authors.forename: Marion
authors.initials: M
authors.lastname: Larroque
authors.forename: Thomas
authors.initials: T
authors.lastname: Moehler
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Rossi
authors.forename: Thierry
authors.initials: T
authors.lastname: Rème
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: Bernard
authors.initials: B
authors.lastname: Klein
mesh_terms: D000368:Aged; D001853:Bone Marrow / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009101:Multiple Myeloma / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D011379:Prognosis; D053668:Syndecan-1 / Q000096:biosynthesis*; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D053668:Syndecan-1; D000099175:Heparanase