Ilan Neta, Elkin Michael, Vlodavsky Israel
Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, P.O. Box 9649, Haifa 31096, Israel.
Int J Biochem Cell Biol. 2006;38(12):2018-39. doi: 10.1016/j.biocel.2006.06.004. Epub 2006 Jul 6.
Heparanase is an endoglycosidase which cleaves heparan sulfate (HS) and hence participates in degradation and remodeling of the extracellular matrix (ECM). Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an invasive phenotype in experimental animals. The enzyme also releases angiogenic factors from the ECM and thereby induces an angiogenic response in vivo. Heparanase upregulation correlates with increased tumor vascularity and poor post-operative survival of cancer patients. Heparanase is synthesized as a 65 kDa inactive precursor that undergoes proteolytic cleavage, yielding 8 and 50 kDa protein subunits that heterodimerize to form an active enzyme. Human heparanase is localized primarily within late endosomes and lysosomes and occasionally on the cell surface and within the cell nucleus. Transcriptional activity of the heparanase promoter is stimulated by demethylation, early growth response 1 (EGR1) transcription factor, estrogen, inflammatory cytokines and inactivation of p53. N-acetylated glycol-split species of heparin as well as siRNA heparanase gene silencing inhibit tumor metastasis and angiogenesis in experimental models. These observations and the unexpected identification of a single functional heparanase, suggest that the enzyme is a promising target for anti-cancer and anti-inflammatory drug development. Heparanase exhibits also non-enzymatic activities, independent of its involvement in ECM degradation and changes in the extracellular microenvironment. For example, cell surface expression of heparanase elicits a firm cell adhesion, reflecting an involvement in cell-ECM interaction. Heparanase enhances Akt signaling and stimulates PI3K- and p38-dependent endothelial cell migration and invasion. It also promotes VEGF expression via the Src pathway. The enzyme may thus activate endothelial cells and elicits angiogenic and survival responses. Studies with heparanase over-expressing transgenic mice revealed that the enzyme functions in normal processes involving cell mobilization, HS turnover, tissue vascularization and remodeling. In this review, we summarize the current status of heparanase research, emphasizing molecular and cellular aspects of the enzyme, including its mode of processing and activation, control of heparanase gene expression, enzymatic and non-enzymatic functions, and causal involvement in cancer metastasis and angiogenesis. We also discuss clinical aspects and strategies for the development of heparanase inhibitors.
乙酰肝素酶是一种内切糖苷酶，可切割硫酸乙酰肝素（HS），从而参与细胞外基质（ECM）的降解和重塑。乙酰肝素酶在人类肿瘤中优先表达，其在肿瘤细胞中的过表达在实验动物中赋予侵袭性表型。该酶还从ECM中释放血管生成因子，从而在体内诱导血管生成反应。乙酰肝素酶上调与肿瘤血管生成增加以及癌症患者术后生存率低相关。乙酰肝素酶最初以65 kDa的无活性前体形式合成，该前体经过蛋白水解切割，产生8 kDa和50 kDa的蛋白质亚基，这些亚基异源二聚化形成活性酶。人乙酰肝素酶主要定位于晚期内体和溶酶体，偶尔定位于细胞表面和细胞核内。乙酰肝素酶启动子的转录活性受到去甲基化、早期生长反应1（EGR1）转录因子、雌激素、炎性细胞因子和p53失活的刺激。N-乙酰化糖裂解型肝素以及小干扰RNA（siRNA）介导的乙酰肝素酶基因沉默在实验模型中抑制肿瘤转移和血管生成。这些观察结果以及单一功能性乙酰肝素酶的意外发现表明，该酶是抗癌和抗炎药物开发的一个有前景的靶点。乙酰肝素酶还表现出非酶活性，与其参与ECM降解和细胞外微环境变化无关。例如，乙酰肝素酶的细胞表面表达引发牢固的细胞黏附，这反映其参与细胞与ECM的相互作用。乙酰肝素酶增强Akt信号传导，并刺激PI3K和p38依赖性内皮细胞迁移和侵袭。它还通过Src途径促进血管内皮生长因子（VEGF）表达。因此，该酶可能激活内皮细胞并引发血管生成和存活反应。对过表达乙酰肝素酶的转基因小鼠的研究表明，该酶在涉及细胞动员、HS周转、组织血管化和重塑的正常过程中发挥作用。在这篇综述中，我们总结了乙酰肝素酶研究的现状，重点介绍了该酶的分子和细胞方面，包括其加工和激活方式、乙酰肝素酶基因表达的调控、酶活性和非酶活性功能，以及在癌症转移和血管生成中的因果关系。我们还讨论了临床方面以及乙酰肝素酶抑制剂的开发策略。
