Nadir Y, Brenner B, Zetser A, Ilan N, Shafat I, Zcharia E, Goldshmidt O, Vlodavsky I
Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
J Thromb Haemost. 2006 Nov;4(11):2443-51. doi: 10.1111/j.1538-7836.2006.02212.x. Epub 2006 Sep 13.
Over-expression of tissue factor (TF) and activation of the coagulation system are common in cancer patients. Heparanase is an endo-beta-D-glucuronidase that cleaves heparan sulfate chains on cell surfaces and in the extracellular matrix, activity that closely correlates with cell invasion, angiogenesis and tumor metastasis. The study was undertaken to investigate the involvement of heparanase in TF expression.
Tumor-derived cell lines were transfected with heparanase cDNA and TF expression was examined. The effect of exogenous addition of active and inactive heparanase on TF expression and activity was studied in tumor cell lines and primary human umbilical vein endothelial cells. TF expression was also explored in heparanase over-expressing transgenic (Tg) mice. Blast cells were collected from acute leukemia patients and TF and heparanase expression levels were analyzed.
Over-expression of heparanase in tumor-derived cell lines resulted in a 2-fold increase in TF expression levels, and a similar trend was observed in heparanase Tg mice in vivo. Likewise, exogenous addition of heparanase to endothelial or tumor-derived cells resulted in enhanced TF expression and activity. Interestingly, TF expression was also induced in response to enzymatically inactive heparanase, suggesting that this effect was independent of heparanase enzymatic activity. The regulatory effect of heparanase on TF expression involved activation of the p38 signaling pathway. A positive correlation between TF expression levels and heparanase activity was found in blasts collected from 22 acute leukemia patients.
Our results indicate that in addition to its well-known function as an enzyme paving a way for invading cells, heparanase also participates in the regulation of TF gene expression and its related coagulation pathways.
组织因子（TF）的过度表达和凝血系统的激活在癌症患者中很常见。乙酰肝素酶是一种内切β-D-葡萄糖醛酸酶，可切割细胞表面和细胞外基质中的硫酸乙酰肝素链，其活性与细胞侵袭、血管生成和肿瘤转移密切相关。本研究旨在探讨乙酰肝素酶在TF表达中的作用。
用乙酰肝素酶cDNA转染肿瘤来源的细胞系，并检测TF表达。在肿瘤细胞系和原代人脐静脉内皮细胞中研究了外源性添加活性和非活性乙酰肝素酶对TF表达和活性的影响。还在乙酰肝素酶过表达的转基因（Tg）小鼠中探索了TF表达。从急性白血病患者中收集原始细胞，分析TF和乙酰肝素酶的表达水平。
肿瘤来源细胞系中乙酰肝素酶的过表达导致TF表达水平增加2倍，在体内的乙酰肝素酶Tg小鼠中也观察到类似趋势。同样，向内皮细胞或肿瘤来源细胞中外源性添加乙酰肝素酶导致TF表达和活性增强。有趣的是，对酶活性无活性的乙酰肝素酶也诱导了TF表达，表明这种作用与乙酰肝素酶的酶活性无关。乙酰肝素酶对TF表达的调节作用涉及p38信号通路的激活。在从22例急性白血病患者收集的原始细胞中发现TF表达水平与乙酰肝素酶活性之间呈正相关。
我们的结果表明，除了其作为为侵袭细胞开辟道路的酶的众所周知的功能外，乙酰肝素酶还参与TF基因表达及其相关凝血途径的调节。
