Periostin is a novel therapeutic target that predicts and regulates glioma malignancy
Periostin is a novel therapeutic target that predicts and regulates glioma malignancy
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DOI：
10.1093/neuonc/nou161
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发表时间：
2015-03-01
期刊：
影响因子：
15.9
通讯作者：
Rostomily, Robert C.
中科院分区：
文献类型：
--
作者：
Mikheev, Andrei M.;Mikheeva, Svetlana A.;Rostomily, Robert C.
背景Periostin是一种分泌型基质细胞蛋白，在上皮-间质转化和肿瘤转移中起重要作用。在胶质母细胞瘤中，与正常脑相比，它高度上调，现有的报告表明在胶质瘤中具有潜在的预后和功能重要性。然而，骨膜蛋白表达的临床意义和与其治疗潜力相关的功能尚未得到充分探讨。通过实时定量PCR和免疫组化检测人胶质瘤细胞和组织中骨膜蛋白的表达水平和模式，并与胶质瘤分级、类型、复发和生存相关。功能测定确定改变骨膜蛋白表达和功能对细胞侵袭、迁移、粘附和胶质瘤干细胞活性和致瘤性的影响。利用TCGA和伦勃朗数据库和配对的复发胶质瘤样本分析骨膜蛋白及其相关基因的预后和功能相关性。在所有级别的成人胶质瘤中，骨膜蛋白表达水平与肿瘤分级和复发直接相关，与生存率呈负相关。仅在IV级胶质瘤中检测到骨膜蛋白的基质沉积。分泌的骨膜蛋白促进胶质瘤细胞的侵袭和粘附，而骨膜蛋白的敲低显著损害异种移植的胶质瘤干细胞的存活。与α v β 3和α v β 5整合素的相互作用促进了粘附和迁移，骨膜蛋白消除了α v β 3/β 5特异性抑制剂西仑吉肽的细胞毒性。以基质蛋白和分泌蛋白为主的骨膜蛋白相关基因特征与患者预后和恶性增加相关的功能基序相对应。骨膜蛋白是神经胶质瘤恶性程度和潜在肿瘤复发的一个可靠标志物。骨膜蛋白抑制后胶质瘤干细胞致瘤性的消除为探索靶向骨膜蛋白的治疗作用提供了支持。
Background. Periostin is a secreted matricellular protein critical for epithelial-mesenchymal transition and carcinoma metastasis. In glioblastoma, it is highly upregulated compared with normal brain, and existing reports indicate potential prognostic and functional importance in glioma. However, the clinical implications of periostin expression and function related to its therapeutic potential have not been fully explored.Methods. Periostin expression levels and patterns were examined in human glioma cells and tissues by quantitative real-time PCR and immunohistochemistry and correlated with glioma grade, type, recurrence, and survival. Functional assays determined the impact of altering periostin expression and function on cell invasion, migration, adhesion, and glioma stem cell activity and tumorigenicity. The prognostic and functional relevance of periostin and its associated genes were analyzed using the TCGA and REMBRANDT databases and paired recurrent glioma samples.Results. Periostin expression levels correlated directly with tumor grade and recurrence, and inversely with survival, in all grades of adult human glioma. Stromal deposition of periostin was detected only in grade IV gliomas. Secreted periostin promoted glioma cell invasion and adhesion, and periostin knockdown markedly impaired survival of xenografted glioma stem cells. Interactions with alpha v beta 3 and alpha v beta 5 integrins promoted adhesion and migration, and periostin abrogated cytotoxicity of the alpha v beta 3/beta 5 specific inhibitor cilengitide. Periostin-associated gene signatures, predominated by matrix and secreted proteins, corresponded to patient prognosis and functional motifs related to increased malignancy.Conclusion. Periostin is a robust marker of glioma malignancy and potential tumor recurrence. Abrogation of glioma stem cell tumorigenicity after periostin inhibition provides support for exploring the therapeutic impact of targeting periostin.