Heparanase 2 Interacts with Heparan Sulfate with High Affinity and Inhibits Heparanase Activity
Heparanase 2 Interacts with Heparan Sulfate with High Affinity and Inhibits Heparanase Activity
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DOI：
10.1074/jbc.m110.116384
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发表时间：
2010-09-03
影响因子：
4.8
通讯作者：
Vlodavsky, Israel
中科院分区：
文献类型：
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作者：
Levy-Adam, Flonia;Feld, Sari;Vlodavsky, Israel
乙酰肝素酶活性与肿瘤转移、血管生成和炎症相关的细胞播散密切相关。乙酰肝素酶在许多血液肿瘤和实体瘤中被诱导表达，与不良预后相关。乙酰肝素酶同源物，称为乙酰肝素酶2（Hpa 2），是基于序列同源性克隆。Hpa 2在生物化学、细胞和临床水平的详细特征迄今尚未报道，其在正常生理和病理疾病中的作用尚不清楚。我们提供的证据表明，不像乙酰肝素酶，Hpa 2不进行蛋白水解加工，并没有表现出典型的乙酰肝素酶的酶活性。值得注意的是，全长Hpa 2c蛋白抑制乙酰肝素酶的酶活性，这可能是由于其对肝素和硫酸乙酰肝素的高亲和力及其与乙酰肝素酶物理缔合的能力。头颈部癌患者中hpa 2表达显著升高，与疾病复发时间延长相关（随访至失败; p = 0.006），与肿瘤细胞向区域淋巴结转移呈负相关（N期; p = 0.03）。hpa 2可能通过减弱乙酰肝素酶的酶活性来抑制肿瘤转移，从而使头颈癌患者获得良好的预后。
Heparanase activity is highly implicated in cell dissemination associated with tumor metastasis, angiogenesis, and inflammation. Heparanase expression is induced in many hematological and solid tumors, associated with poor prognosis. Heparanase homolog, termed heparanase 2 (Hpa2), was cloned based on sequence homology. Detailed characterization of Hpa2 at the biochemical, cellular, and clinical levels has not been so far reported, and its role in normal physiology and pathological disorders is obscure. We provide evidence that unlike heparanase, Hpa2 is not subjected to proteolytic processing and exhibits no enzymatic activity typical of heparanase. Notably, the full-length Hpa2c protein inhibits heparanase enzymatic activity, likely due to its high affinity to heparin and heparan sulfate and its ability to associate physically with heparanase. Hpa2 expression was markedly elevated in head and neck carcinoma patients, correlating with prolonged time to disease recurrence (follow-up to failure; p = 0.006) and inversely correlating with tumor cell dissemination to regional lymph nodes (N-stage; p = 0.03). Hpa2 appears to restrain tumor metastasis, likely by attenuating heparanase enzymatic activity, conferring a favorable outcome of head and neck cancer patients.