Heparanase promotes glioma progression via enhancing CD24 expression
Heparanase promotes glioma progression via enhancing CD24 expression
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乙酰肝素酶通过增强 CD24 表达促进神经胶质瘤进展
DOI：
10.1002/ijc.32375
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发表时间：
2019-09-15
影响因子：
6.4
通讯作者：
Yang, Xiaojun
中科院分区：
文献类型：
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作者：
Barash, Uri;Spyrou, Argyris;Yang, Xiaojun
乙酰肝素酶是一种内切β-D-葡萄糖醛酸酶，其切割硫酸乙酰肝素蛋白聚糖的硫酸乙酰肝素（HS）侧链。令人信服的证据将乙酰肝素酶水平与肿瘤形成的所有步骤联系在一起，包括肿瘤起始、生长、转移和化学抗性，可能涉及信号传导途径和基因转录的增强。为了揭示乙酰肝素酶促肿瘤发生的分子机制，我们在U87人胶质瘤细胞中建立了诱导型（Tet-on）系统，并应用基因阵列方法来鉴定与乙酰肝素酶诱导相关的基因。我们发现，CD 24，粘蛋白样细胞粘附蛋白，是一致上调乙酰肝素酶和乙酰肝素酶剪接变异体缺乏酶活性，而乙酰肝素酶基因沉默与CD 24表达减少。胶质瘤患者中乙酰肝素酶和CD 24免疫染色的相似模式进一步证实了这一发现（Pearson相关性; R = 0.66，p = 0.00001）。值得注意的是，CD 24的过表达刺激胶质瘤细胞迁移、侵袭、软琼脂集落形成和小鼠肿瘤生长，表明CD 24的功能促进肿瘤生长。同样，抗CD 24中和单克隆抗体可减弱神经胶质瘤肿瘤的生长，并且在用针对L1细胞粘附分子（L1 CAM）（CD 24的配体）的中和mAb治疗的小鼠中也观察到类似的抑制作用。重要的是，对于高级别和低级别胶质瘤，发现肝素酶高/CD 24高肿瘤与肝素酶高/CD 24低肿瘤的患者生存期显著较短（p = 0.02）。因此，我们的研究结果揭示了一种新的乙酰肝素酶-CD 24-L1 CAM轴，在胶质瘤肿瘤发生中起着重要作用。
Heparanase is an endo-beta-d-glucuronidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans. Compelling evidence tie heparanase levels with all steps of tumor formation including tumor initiation, growth, metastasis and chemo-resistance, likely involving augmentation of signaling pathways and gene transcription. In order to reveal the molecular mechanism(s) underlying the protumorigenic properties of heparanase, we established an inducible (Tet-on) system in U87 human glioma cells and applied gene array methodology in order to identify genes associated with heparanase induction. We found that CD24, a mucin-like cell adhesion protein, is consistently upregulated by heparanase and by heparanase splice variant devoid of enzymatic activity, whereas heparanase gene silencing was associated with decreased CD24 expression. This finding was further substantiated by a similar pattern of heparanase and CD24 immunostaining in glioma patients (Pearson's correlation; R = 0.66, p = 0.00001). Noteworthy, overexpression of CD24 stimulated glioma cell migration, invasion, colony formation in soft agar and tumor growth in mice suggesting that CD24 functions promote tumor growth. Likewise, anti-CD24 neutralizing monoclonal antibody attenuated glioma tumor growth, and a similar inhibition was observed in mice treated with a neutralizing mAb directed against L1 cell adhesion molecule (L1CAM), a ligand for CD24. Importantly, significant shorter patient survival was found in heparanase-high/CD24-high tumors vs. heparanase-high/CD24-low tumors for both high-grade and low-grade glioma (p = 0.02). Our results thus uncover a novel heparanase-CD24-L1CAM axis that plays a significant role in glioma tumorigenesis.