期刊
ONCOTARGET
卷 7, 期 35, 页码 56958-56975出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10925
关键词
cdc42; glioblastoma; migration; invasion; IQGAP1 and pFAK
资金
- Canadian Institute of Health Research [MOP 74610]
- b.r.a.i.n. child, Meagan's Walk (Meagan Bebenek Research Institute)
- Laurie Berman and Wiley Family funds for brain tumour research
- National Cancer Institute [CA1428580, CA86335, CA163722]
- Winship and Emory Integrated Cellular Imaging Core
- NIH/NCI [P30CA138292]
Cdc42 is a Rho-GTPase which plays a major role in regulating cell polarity and migration by specifying the localization of filopodia. However, the role of Cdc42 in GBM invasion has not been thoroughly investigated. We generated stable doxycycline-inducible clones expressing wild type (WT)-, constitutively active (CA)-, and dominant negative (DN)-Cdc42 in three different human glioma cell lines. Expression of CA-Cdc42 significantly increased the migration and invasive properties of malignant glioma cells compared to WT and DN-Cdc42 cell clones, and this was accompanied by a greater number of filopodia and focal adhesion structures which co-localize with phosphorylated focal adhesion kinase (FAK). By mass spectrometry and immunoprecipitation studies, we demonstrated that activated Cdc42 binds to IQGAP1. When implanted orthotopically in mice, the CA-Cdc42 expressing glioma cells exhibited enhanced local migration and invasion, and led to larger tumors, which significantly reduced survival. Using the Cancer Genome Atlas dataset, we determined that high Cdc42 expression is associated with poorer progression free survival, and that Cdc42 expression is highest in the proneural and neural subgroups of GBM. In summary, our studies demonstrate that activated Cdc42 is a critical determinant of the migratory and invasive phenotype of malignant gliomas, and that its effect may be mediated, at least in part, through its interaction with IQGAP1 and phosphorylated FAK.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据