Human glioblastomas overexpress ADAMTS-5 that degrades brevican
Human glioblastomas overexpress ADAMTS-5 that degrades brevican
复制标题
DOI：
10.1007/s00401-005-1032-6
复制
发表时间：
2005-09-01
影响因子：
12.7
通讯作者：
Okada, Y
中科院分区：
文献类型：
--
作者：
Nakada, M;Miyamori, H;Okada, Y
brevican是成人脑组织中主要的蛋白聚糖之一，其Glu(395)-Ser（396）键的选择性裂解被认为是胶质瘤细胞侵袭的重要因素。我们之前的生化研究表明，ADAMTS-4是ADAMTS（一种具有血栓反应蛋白基序的崩解素和金属蛋白酶）家族的成员，具有这种活性。在本研究中，我们在细胞水平上检测了ADAMTS-1、-4和-5的短叶草素降解活性，以及它们在人胶质瘤组织中的表达和定位。在表达ADAMTS-4或ADAMTS-5的293T中，布雷维蛋白以相同的模式被切割成两个主要片段，但在表达ADAMTS-1的293T中没有观察到这种降解。实时定量PCR检测这些ADAMTS种的表达水平时，与正常脑组织相比，胶质母细胞瘤组织中只有ADAMTS-5过表达（P < 0.05）。原位杂交和免疫组织化学表明，ADAMTS-5主要在胶质母细胞瘤细胞中表达。在胶质瘤细胞系中强制表达ADAMTS-5刺激细胞侵袭。这些结果首次证实了ADAMTS-5能够降解布雷维肽并在胶质母细胞瘤细胞中过表达，提示ADAMTS-5可能通过切割布雷维肽参与胶质瘤细胞的侵袭。
Selective cleavage of the Glu(395)-Ser(396) bond of brevican, one of the major proteoglycans in adult brain tissues, is thought to be important for glioma cell invasion. Our previous biochemical study demonstrated that ADAMTS-4, a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, has such an activity. In the present study, we examined brevican-degrading activities of ADAMTS-1, -4 and -5 at the cellular level, and their expression and localization in human glioma tissues. In 293T transfectants expressing ADAMTS-4 or ADAMTS-5, brevican was cleaved into two major fragments in an identical pattern, but no such degradation was observed with ADAMTS-1 transfectants. When the expression levels of these ADAMTS species were examined by real-time quantitative PCR, only ADAMTS-5 was found to be overexpressed in glioblastoma tissues compared to control normal brain tissues (P < 0.05). In situ hybridization and immunohistochemistry demonstrated that ADAMTS-5 is expressed predominantly in glioblastoma cells. Forced expression of ADAMTS-5 in glioma cell lines stimulated cell invasion. These results demonstrate for the first time that ADAMTS-5 is capable of degrading brevican and is overexpressed in glioblastoma cells, and suggest that ADAMTS-5 may play a role in glioma cell invasion through the cleavage of brevican.