Discoidin domain receptor-1a (DDR1a) promotes glioma cell invasion and adhesion in association with matrix metalloproteinase-2
Discoidin domain receptor-1a (DDR1a) promotes glioma cell invasion and adhesion in association with matrix metalloproteinase-2
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DOI：
10.1007/s11060-005-6874-1
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发表时间：
2006-02-01
影响因子：
3.9
通讯作者：
Nagavarapu, U
中科院分区：
文献类型：
--
作者：
Ram, R;Lorente, G;Nagavarapu, U
神经胶质瘤细胞的侵袭涉及侵袭的肿瘤细胞与细胞外基质（ECM）的附着、ECM组分的破坏以及随后的细胞渗透到邻近的脑结构中。盘状结构域受体1（DDR 1）酪氨酸激酶构成了一个新的受体家族，其特征在于胞外域（盘状结构域-I）中的独特结构。这些细胞表面受体与几种胶原结合并促进细胞粘附。DDR 1在多形性胶质母细胞瘤中的表达和功能知之甚少。在这项研究中，我们证明，DDR 1过表达的胶质瘤组织中使用cDNA阵列，免疫组化和Western印迹分析。DDR 1的两种剪接变体（DDR 1a和DDR 1b）的功能比较揭示了基于细胞的胶质瘤模型中的新差异。DDR 1a或DDR 1b的过表达引起细胞附着增加。然而，过表达DDR 1a的胶质瘤细胞显示增强的侵袭和迁移。我们还检测到DDR 1a过表达细胞中基质金属蛋白酶-2水平的增加，通过酶谱法测定。使用MMP抑制剂抑制MMP活性可抑制DDR 1a刺激的细胞侵袭。类似地，针对DDR 1的抗体减少DDR 1a介导的侵袭以及增强DDR 1a和DDR 1b过表达细胞的粘附。这些结果表明，DDR 1a在诱导肿瘤细胞粘附和侵袭中起关键作用，并且这种侵袭表型是由基质金属蛋白酶-2激活引起的。
Invasion of glioma cells involves the attachment of invading tumor cells to extracellular matrix (ECM), disruption of ECM components, and subsequent cell penetration into adjacent brain structures. Discoidin domain receptor 1 (DDR1) tyrosine kinases constitute a novel family of receptors characterized by a unique structure in the ectodomain (discoidin-I domain). These cell surface receptors bind to several collagens and facilitate cell adhesion. Little is known about DDR1 expression and function in glioblastoma multiforme. In this study we demonstrate that DDR1 is overexpressed in glioma tissues using cDNA arrays, immunohistochemistry and Western blot analysis. Functional comparison of two splice variants of DDR1 (DDR1a and DDR1b) reveal novel differences in cell based glioma models. Overexpression of either DDR1a or DDR1b caused increased cell attachment. However, glioma cells overexpressing DDR1a display enhanced invasion and migration. We also detect increased levels of matrix metalloproteinase-2 in DDR1a overexpressing cells as measured by zymography. Inhibition of MMP activity using MMP inhibitor suppressed DDR1a stimulated cell-invasion. Similarly, an antibody against DDR1 reduced DDR1a mediated invasion as well as the enhanced adhesion of DDR1a and DDR1b overexpressing cells. These results suggest that DDR1a plays a critical role in inducing tumor cell adhesion and invasion, and this invasive phenotype is caused by activation of matrix metalloproteinase-2.