Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma
Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma
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DOI：
10.1182/blood-2006-08-043232
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发表时间：
2007-06-01
期刊：
影响因子：
20.3
通讯作者：
Klein, Bernard
中科院分区：
文献类型：
--
作者：
Mahtouk, Karene;Hose, Dirk;Klein, Bernard
硫酸乙酰肝素（HS）蛋白聚糖，syndecan-1，通过在多发性骨髓瘤（MM）细胞（MMCs）表面浓缩肝素结合生长因子在MM中起着重要作用。使用Affyssin微阵列和实时逆转录聚合酶链反应（RTPCR），我们表明，编码乙酰肝素酶（HPSE），一种酶，切割HS链，表达的基因由19个骨髓瘤细胞系（HMCLs）的11。在HSPE-（pos）HMCL中，syndecan-1基因表达和可溶性syndecan-1的产生显著增加，与膜syndecan-1的表达不同。通过siRNA敲低HPSE导致syndecan-1基因表达和可溶性syndecan-1产生减少，而不影响膜syndecan-1表达。因此，HPSE影响syndecan-1的表达和脱落。与HMCL相反，HPSE仅在39个原发性MMC样品中的4个中表达，而在39个骨髓（BM）微环境样品中的36个中表达。在后者中，HPSE在多形核细胞和T细胞中以中等水平表达;它在单核细胞和破骨细胞中高度表达。在HMCL和患者样本中，在蛋白质水平上验证了Affyellow数据。我们首次报道了一种主要在骨髓环境中表达的基因（le，HSPE）与接受大剂量化疗和干细胞移植治疗的新诊断骨髓瘤患者的无事件生存期缩短相关。我们的研究表明，HPSE的临床抑制剂可能对MM患者有益。
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 (RTPCR), 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 (le, 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.