Salhia Bodour, Tran Nhan L, Chan Amanda, Wolf Amparo, Nakada Mitsutoshi, Rutka Fiona, Ennis Matthew, McDonough Wendy S, Berens Michael E, Symons Marc, Rutka James T
Arthur and Sonia Labatt Brain Tumor Research Centre, Cancer and Cell Biology Division, The Hospital for Sick Children, the University of Toronto, Toronto, Canada.
Am J Pathol. 2008 Dec;173(6):1828-38. doi: 10.2353/ajpath.2008.080043. Epub 2008 Nov 13.
Malignant gliomas are characterized by their ability to invade normal brain tissue. We have previously shown that the small GTPase Rac1 plays a role in both migration and invasion in gliomas. Here, we aim to identify Rac-activating guanine nucleotide exchange factors (GEFs) that mediate glioblastoma invasiveness. Using a brain tumor expression database, we identified three GEFs, Trio, Ect2, and Vav3, that are expressed at higher levels in glioblastoma versus low-grade glioma. The expression of these GEFs is also associated with poor patient survival. Quantitative real-time polymerase chain reaction and immunohistochemical analyses on an independent set of tumors confirmed that these GEFs are overexpressed in glioblastoma as compared with either nonneoplastic brain or low-grade gliomas. In addition, depletion of Trio, Ect2, and Vav3 by siRNA oligonucleotides suppresses glioblastoma cell migration and invasion. Depletion of either Ect2 or Trio also reduces the rate of cell proliferation. These results suggest that targeting GEFs may present novel strategies for anti-invasive therapy for malignant gliomas.
恶性胶质瘤的特征在于其侵袭正常脑组织的能力。我们之前已经表明，小GTP酶Rac1在胶质瘤的迁移和侵袭中均发挥作用。在此，我们旨在鉴定介导胶质母细胞瘤侵袭性的Rac激活鸟嘌呤核苷酸交换因子（GEF）。利用脑肿瘤表达数据库，我们鉴定出三种GEF，即Trio、Ect2和Vav3，它们在胶质母细胞瘤中的表达水平高于低级别胶质瘤。这些GEF的表达也与患者的不良生存相关。对一组独立肿瘤进行的定量实时聚合酶链反应和免疫组织化学分析证实，与非肿瘤性脑或低级别胶质瘤相比，这些GEF在胶质母细胞瘤中过表达。此外，通过小干扰RNA寡核苷酸耗尽Trio、Ect2和Vav3可抑制胶质母细胞瘤细胞的迁移和侵袭。耗尽Ect2或Trio也会降低细胞增殖速率。这些结果表明，靶向GEF可能为恶性胶质瘤的抗侵袭治疗提供新策略。
