Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and Activity
Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and Activity
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DOI：
10.1074/jbc.m110.183277
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发表时间：
2011-02-25
影响因子：
4.8
通讯作者：
Sanderson, Ralph D.
中科院分区：
文献类型：
--
作者：
Ramani, Vishnu C.;Yang, Yang;Sanderson, Ralph D.
肝细胞生长因子（HGF）是一种肝素结合细胞因子，可增强许多肿瘤类型的生长、运动和血管生成，包括多发性骨髓瘤，在多发性骨髓瘤中通常高度表达。然而，很少有人知道是什么控制这些肿瘤中的HGF水平和活性。骨髓瘤患者骨髓活检的评估显示，HGF和乙酰肝素酶（一种已知促进肿瘤侵袭行为的内切葡萄糖醛酸酶）水平之间存在强正相关性。在体外，加入重组乙酰肝素酶的骨髓瘤细胞或转染骨髓瘤细胞系的cDNA乙酰肝素酶显着增加肿瘤细胞的表达和分泌的生物活性的HGF。脱落多配体蛋白聚糖-1，其在骨髓瘤中的水平也通过乙酰肝素酶表达而增强，结合分泌的HGF。这种多配体蛋白聚糖-1-HGF复合物是有活性的，如其通过c-Met（HGF的细胞表面受体）刺激旁分泌信号传导的能力所示。令人惊讶的是，乙酰肝素酶活性不是肿瘤细胞上调HGF表达所必需的。这与乙酰肝素酶介导的增强的多配体蛋白聚糖-1脱落相反，其确实需要酶的活性。这表明乙酰肝素酶内的两个不同的功能结构域（酶活性位点和单独的位点）有助于导致增强的HGF信号传导的事件。这些发现证明了一种驱动HGF途径的新机制，其中乙酰肝素酶刺激HGF表达和多配体蛋白聚糖-1脱落的增加以增强HGF信号传导。这项工作还提供了进一步的机制洞察乙酰肝素酶在驱动侵袭性肿瘤进展的动态作用。
Hepatocyte growth factor (HGF) is a heparin-binding cytokine that enhances growth, motility, and angiogenesis of many tumor types, including multiple myeloma where it is often highly expressed. However, little is known regarding what controls HGF level and activity in these tumors. Evaluation of bone marrow biopsies from myeloma patients revealed a strong positive correlation between the levels of HGF and heparanase, an endoglucuronidase known to promote aggressive tumor behavior. In vitro, addition of recombinant heparanase to myeloma cells or transfection of myeloma cell lines with the cDNA for heparanase significantly increased tumor cell expression and secretion of biologically active HGF. Shed syndecan-1, whose levels in myeloma are also enhanced by heparanase expression, binds to secreted HGF. This syndecan-1-HGF complex is active as shown by its ability to stimulate paracrine signaling via c-Met, the cell surface receptor for HGF. Surprisingly, heparanase enzyme activity was not required for up-regulation of HGF expression by the tumor cells. This is in contrast to the heparanase-mediated enhanced syndecan-1 shedding, which does require activity of the enzyme. This suggests that two different functional domains within the heparanase enzyme (the enzyme active site and a separate site) contribute to events leading to enhanced HGF signaling. These findings demonstrate a novel mechanism driving the HGF pathway whereby heparanase stimulates an increase in both HGF expression and syndecan-1 shedding to enhance HGF signaling. This work also provides further mechanistic insight into the dynamic role of heparanase in driving aggressive tumor progression.