R132H mutation in IDH1 gene reduces proliferation, cell survival and invasion of human glioma by downregulating Wnt/β-catenin signaling

被引：58

作者：

Cui, Daming ^{[1
]}

Ren, Jie ^{[1
]}

Shi, Jinlong ^{[2
]}

Feng, Lijing ^{[3
]}

Wang, Ke ^{[1
]}

Zeng, Tao ^{[1
]}

Jin, Yi ^{[1
]}

Gao, Liang ^{[1
]}

机构：

[1] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Neurosurg, Shanghai 200072, Peoples R China

[2] Nantong Univ, Affiliated Hosp, Dept Neurosurg, 20 Xisi Rd, Nantong 226001, Jiangsu, Peoples R China

[3] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Pathol, Shanghai, Peoples R China

来源：

INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY | 2016年 / 73卷

基金：

中国国家自然科学基金;

关键词：

Mutant IDH1-R132H; beta-Catenin; Glioma; Proliferation; Invasion; BETA-CATENIN; MALIGNANT GLIOMAS; GLIOBLASTOMA; SUPPRESSES; PATHWAYS; GROWTH;

D O I：

10.1016/j.biocel.2016.02.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene commonly occur in gliomas. Remarkably, the R132H mutation in IDH1 (IDH1-R132H) is associated with better prognosis and increased survival than patients lacking this mutation. The molecular mechanism underlying this phenomenon is largely unknown. In this study, we investigated potential cross-talk between IDH1-R132H and Wnt/beta-catenin signaling in regulating the cellular properties of human glioma. Although aberrant nuclear accumulation of beta-catenin is linked to the malignant progression of gliomas, its association with IDH1 remains unknown. We identified an inverse correlation between IDH1-R132H and the expression and activity of I3-catenin in human gliomas. In addition, overexpression of IDH1-R132H in glioblastoma cell lines U87 and U251 led to reduced cell proliferation, migration and invasion, accompanied by increased apoptosis. At the molecular level, we detected a significant reduction in the expression, nuclear accumulation and activity of p-catenin following overexpression of IDH1-R132H. A microarray-based comparison of gene expression indicated that several mediators, effectors and targets of Wnt/beta-catenin signaling are down regulated, while negative regulators are upregulated in IDH1-R132H gliomas. Further, overexpression of I3-catenin in IDH1-R132H glioma cells restored the cellular phenotype induced by this mutation. Specifically, P-catenin abrogated the decrease in proliferation, invasion and migration, and the increase in apoptosis, triggered by overexpression of IDH1-R132H. Finally, we demonstrate that xenografts of IDH1-R132H overexpressing U87 cells can significantly decrease the growth of tumors in vivo. Altogether, our results strongly suggest that the R132H mutation in IDH1 serves a tumor suppressor function in human glioma by negatively regulating Wntill-catenin signaling. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：72 / 81

页数：10

共 39 条

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