Yang Yang, Macleod Veronica, Miao Hua-Quan, Theus Allison, Zhan Fenghuang, Shaughnessy John D, Sawyer Jeffrey, Li Jin-Ping, Zcharia Eyal, Vlodavsky Israel, Sanderson Ralph D
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
J Biol Chem. 2007 May 4;282(18):13326-33. doi: 10.1074/jbc.M611259200. Epub 2007 Mar 8.
When shed from the cell surface, the heparan sulfate proteoglycan syndecan-1 can facilitate the growth, angiogenesis, and metastasis of tumors. Here we report that tumor cell expression of heparanase, an enzyme known to be a potent promoter of tumor progression and metastasis, regulates both the level and location of syndecan-1 within the tumor microenvironment by enhancing its synthesis and subsequent shedding from the tumor cell surface. Heparanase regulation of syndecan-1 is detected in both human myeloma and breast cancer cell lines. This regulation requires the presence of active enzyme, because mutated forms of heparanase lacking heparan sulfate-degrading activity failed to influence syndecan-1 expression or shedding. Removal of heparan sulfate from the cell surface using bacterial heparitinase dramatically accelerated syndecan-1 shedding, suggesting that the effects of heparanase on syndecan-1 expression by tumor cells may be due, at least in part, to enzymatic removal or reduction in the size of heparan sulfate chains. Animals bearing tumors formed from cells expressing high levels of heparanase or animals transgenic for heparanase expression exhibited elevated levels of serum syndecan-1 as compared with controls, indicating that heparanase regulation of syndecan-1 expression and shedding can occur in vivo and impact cancer progression and perhaps other pathological states. These results reveal a new mechanism by which heparanase promotes an aggressive tumor phenotype and suggests that heparanase and syndecan-1 act synergistically to fine tune the tumor microenvironment and ensure robust tumor growth.
当硫酸乙酰肝素蛋白聚糖syndecan-1从细胞表面脱落时，它可以促进肿瘤的生长、血管生成和转移。在此我们报告，肿瘤细胞表达的乙酰肝素酶（一种已知的肿瘤进展和转移的强力促进因子）通过增强其合成以及随后从肿瘤细胞表面脱落，来调节肿瘤微环境中syndecan-1的水平和位置。在人骨髓瘤和乳腺癌细胞系中均检测到乙酰肝素酶对syndecan-1的调节作用。这种调节需要活性酶的存在，因为缺乏硫酸乙酰肝素降解活性的乙酰肝素酶突变形式未能影响syndecan-1的表达或脱落。使用细菌类肝素酶从细胞表面去除硫酸乙酰肝素可显著加速syndecan-1的脱落，这表明乙酰肝素酶对肿瘤细胞syndecan-1表达的影响可能至少部分归因于硫酸乙酰肝素链的酶促去除或大小减小。与对照组相比，由表达高水平乙酰肝素酶的细胞形成肿瘤的动物或转基因表达乙酰肝素酶的动物血清syndecan-1水平升高，这表明乙酰肝素酶对syndecan-1表达和脱落的调节可在体内发生，并影响癌症进展以及可能的其他病理状态。这些结果揭示了乙酰肝素酶促进侵袭性肿瘤表型的一种新机制，并表明乙酰肝素酶和syndecan-1协同作用以微调肿瘤微环境并确保强劲的肿瘤生长。
