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潜伏型乙酰肝素酶促进VLA-4介导的黑色素瘤细胞黏附,并成为肝素干扰转移进程的一个相关靶点。

Latent heparanase facilitates VLA-4-mediated melanoma cell binding and emerges as a relevant target of heparin in the interference with metastatic progression.

作者信息

Gerber Ursula, Hoß Sebastian G, Shteingauz Anna, Jüngel Eva, Jakubzig Bastian, Ilan Neta, Blaheta Roman, Schlesinger Martin, Vlodavsky Israel, Bendas Gerd

机构信息

Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.

Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.

出版信息

Semin Thromb Hemost. 2015 Mar;41(2):244-54. doi: 10.1055/s-0035-1544229. Epub 2015 Feb 15.

Abstract

Heparanase is an endo-β-glucuronidase that enzymatically cleaves heparan sulfates (HS) and heparan sulfate proteoglycan (HSPG) structures. Heparanase expression levels by tumors were correlated with cell invasion, angiogenic activity, and poor prognosis. Heparanase can also possess pro-tumorigenic effects independent of its enzymatic activity. Using human melanoma MV3 cells, we demonstrate that latent heparanase activates in a tightly temporary-regulated manner the binding function of the integrin very late antigen-4 (VLA-4), an important component in the metastatic spread of melanoma cells. shRNA-mediated knockdown of syndecan-4 (SDC-4) indicated that this proteoglycan is the key element to convey heparanase binding via focal adhesion complex formation, detected by vinculin staining, to an upregulated VLA-4 binding function. This inside-out signaling pathway of VLA-4 involved activated FAK and Akt, but apparently not PKCα/δ. VLA-4, however, appears representative of other integrins which together impact the heparanase/integrin activation axis in tumorigenicity. Biosensor measurements provided an insight as to how heparin can interfere with this activation process. While low-molecular-weight heparin (LMWH) cannot replace heparanase bound to SDC-4, LMWH can compete with SDC-4 binding of heparanase. Since blockade of heparanase by LMWH has functional consequences for reduced VLA-4 binding, latent heparanase appears as a novel, so far unnoticed target of heparin, underlying its antimetastatic activity.

摘要

乙酰肝素酶是一种内切-β-葡萄糖醛酸酶,可酶解硫酸乙酰肝素(HS)和硫酸乙酰肝素蛋白聚糖(HSPG)结构。肿瘤的乙酰肝素酶表达水平与细胞侵袭、血管生成活性及不良预后相关。乙酰肝素酶还可具有独立于其酶活性的促肿瘤发生作用。利用人黑色素瘤MV3细胞,我们证明潜伏的乙酰肝素酶以严格的时间调控方式激活整合素极迟抗原-4(VLA-4)的结合功能,VLA-4是黑色素瘤细胞转移扩散中的一个重要成分。短发夹RNA介导的syndecan-4(SDC-4)敲低表明,这种蛋白聚糖是通过黏着斑复合物形成(通过纽蛋白染色检测)将乙酰肝素酶结合传递至上调的VLA-4结合功能的关键元件。VLA-4的这种由内向外信号通路涉及激活的黏着斑激酶(FAK)和蛋白激酶B(Akt),但显然不涉及蛋白激酶Cα/δ(PKCα/δ)。然而,VLA-4似乎代表了其他整合素,它们共同影响肿瘤发生中的乙酰肝素酶/整合素激活轴。生物传感器测量为肝素如何干扰这一激活过程提供了见解。虽然低分子量肝素(LMWH)不能取代与SDC-4结合的乙酰肝素酶,但LMWH可与乙酰肝素酶的SDC-4结合竞争。由于LMWH对乙酰肝素酶的阻断对降低VLA-4结合具有功能影响,潜伏的乙酰肝素酶似乎是肝素的一个新的、迄今未被注意到的靶点,这是其抗转移活性的基础。

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