Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate
Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate
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DOI：
10.1038/nchembio.2007.41
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发表时间：
2007-12-01
影响因子：
14.8
通讯作者：
Li, Jin-Ping
中科院分区：
文献类型：
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作者：
Galvis, Martha L. Escobar;Jia, Juan;Li, Jin-Ping
硫酸乙酰肝素蛋白聚糖（HSPG）与动物发育和体内平衡中的许多重要蛋白质相互作用（1-3）。乙酰肝素酶在正常组织中表达并在血管生成、癌症和炎症中上调，选择性地切割HS链中的β-葡萄糖醛酸苷键。在先前的研究中，我们在小鼠中转基因过表达乙酰肝素酶，以评估乙酰肝素酶对HS代谢的总体影响。代谢标记证实了HS在体内的广泛片段化（4，5）。在目前的研究中，我们发现在显示出乙酰肝素酶过度表达的肝脏中，HSPG周转随着HS N-和O-硫酸化的上调而沿着加速，从而产生没有HS典型结构域结构的肝素样链。乙酰肝素酶在其他小鼠器官和人类肿瘤中的过度表达与HS的6-O-硫酸化增加相关，而结构域结构是保守的。高度硫酸化的HS片段强烈促进与成纤维细胞生长因子1（FGF 1）或FGF 2和FGF受体1的三元复合物的形成。因此，乙酰肝素酶有助于调节HS的生物合成的方式，可以促进生长因子的作用，在肿瘤血管生成和转移。
Heparan sulfate proteoglycans (HSPGs) interact with numerous proteins of importance in animal development and homeostasis(1-3). Heparanase, which is expressed in normal tissues and upregulated in angiogenesis, cancer and inflammation, selectively cleaves beta-glucuronidic linkages in HS chains. In a previous study, we transgenically overexpressed heparanase in mice to assess the overall effects of heparanase on HS metabolism. Metabolic labeling confirmed extensive fragmentation of HS in vivo(4,5). In the current study we found that in liver showing excessive heparanase overexpression, HSPG turnover is accelerated along with upregulation of HS N- and O- sulfation, thus yielding heparin-like chains without the domain structure typical of HS. Heparanase overexpression in other mouse organs and in human tumors correlated with increased 6-O-sulfation of HS, whereas the domain structure was conserved. The heavily sulfated HS fragments strongly promoted formation of ternary complexes with fibroblast growth factor 1 (FGF1) or FGF2 and FGF receptor 1. Heparanase thus contributes to regulation of HS biosynthesis in a way that may promote growth factor action in tumor angiogenesis and metastasis.