Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma.
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.
Mahtouk
Karène
K
Institute of Research in Biology, Centre Hospitalier Universitaire Montpellier, 99 rue Puech Villa, 34197 Montpellier Cedex 5, France.
Hose
Dirk
D
Raynaud
Pierre
P
Hundemer
Michael
M
Jourdan
Michel
M
Jourdan
Eric
E
Pantesco
Veronique
V
Baudard
Marion
M
De Vos
John
J
Larroque
Marion
M
Moehler
Thomas
T
Rossi
Jean-Francois
JF
Rème
Thierry
T
Goldschmidt
Hartmut
H
Klein
Bernard
B
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
D005966:Glucuronidase; D053668:Syndecan-1; D000099175:Heparanase