Purpose

High-grade gliomas (HGG) remain one of the most aggressive tumors, which is primarily due to its diffuse infiltrative nature. Serine proteases and metalloproteases are known to play key roles in cellular migration and invasion mechanisms. SPINT2, also known as HAI-2, is an important serine protease inhibitor that can affect MET signaling. SPINT2 has been found to be frequently downregulated in various tumors, whereby hypermethylation of its promoter appears to serve as a common mechanism. Here, we assessed the clinical relevance of SPINT2 expression and promoter hypermethylation in pediatric and adult HGG and explored its functional role.

Methods

A series of 371 adult and 77 pediatric primary HGG samples was assessed for SPINT2 protein expression (immunohistochemistry) and promoter methylation (methylation-specific PCR) patterns. After SPINT2 knockdown and knock-in in adult and pediatric HGG cell lines, a variety of in vitro assays was carried out to determine the role of SPINT2 in glioma cell viability and invasion, as well as their mechanistic associations with metalloprotease activities.

Results

We found that SPINT2 protein expression was frequently absent in adult (85.3%) and pediatric (100%) HGG samples. The SPINT2 gene promoter was found to be hypermethylated in approximately half of both adult and pediatric gliomas. Through functional assays we revealed a suppressor activity of SPINT2 in glioma cell proliferation and viability, as well as in their migration and invasion. These functions appear to be mediated in part by MMP2 expression and activity.

Conclusions

We conclude that dysregulation of SPINT2 is a common event in both pediatric and adult HGG, in which SPINT2 may act as a tumor suppressor.

中文翻译：

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在神经胶质瘤中，SPINT2表达的缺失经常发生，从而导致通过MMP2的生长和侵袭增加。

目的

高度神经胶质瘤（HGG）仍然是最具侵袭性的肿瘤之一，这主要是由于其具有弥漫性浸润性。已知丝氨酸蛋白酶和金属蛋白酶在细胞迁移和侵袭机制中起关键作用。SPINT2，也称为HAI-2，是一种重要的丝氨酸蛋白酶抑制剂，可影响MET信号传导。已经发现SPINT2在各种肿瘤中经常被下调，由此其启动子的高甲基化似乎是一种常见的机制。在这里，我们评估了儿童和成人HGG中SPINT2表达和启动子高甲基化的临床相关性，并探讨了其功能作用。

方法

评估了371个成人和77个儿科原发性HGG样品的SPINT2蛋白表达（免疫组织化学）和启动子甲基化（甲基化特异性PCR）模式。在成年和小儿HGG细胞系中敲除和敲除SPINT2后，进行了多种体外测定，以确定SPINT2在神经胶质瘤细胞活力和侵袭中的作用，以及它们与金属蛋白酶活性的机制关联。

结果

我们发现成人（85.3％）和儿童（100％）HGG样本中经常缺少SPINT2蛋白表达。该SPINT2基因启动子被发现在大约一半的成人和儿童脑胶质瘤的被甲基化。通过功能测定，我们揭示了SPINT2在神经胶质瘤细胞增殖和活力以及它们的迁移和侵袭中具有抑制活性。这些功能似乎部分由MMP2表达和活性介导。

结论

我们得出结论，SPINT2的失调在小儿和成人HGG中都是常见事件，其中SPINT2可能充当肿瘤抑制因子。