title: R132H mutation in IDH1 gene reduces proliferation, cell survival and invasion of human glioma by downregulating Wnt/β-catenin signaling.
abstract: 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/β-catenin signaling in regulating the cellular properties of human glioma. Although aberrant nuclear accumulation of β-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 β-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 β-catenin following overexpression of IDH1-R132H. A microarray-based comparison of gene expression indicated that several mediators, effectors and targets of Wnt/β-catenin signaling are downregulated, while negative regulators are upregulated in IDH1-R132H gliomas. Further, overexpression of β-catenin in IDH1-R132H glioma cells restored the cellular phenotype induced by this mutation. Specifically, β-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 Wnt/β-catenin signaling.
authors: Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China.
authors: Daming
authors: D
authors: Cui
authors: Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China.
authors: Jie
authors: J
authors: Ren
authors: Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong 226001, Jiangsu Province, People's Republic of China.
authors: Jinlong
authors: J
authors: Shi
authors: Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors: Lijing
authors: L
authors: Feng
authors: Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China.
authors: Ke
authors: K
authors: Wang
authors: Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China.
authors: Tao
authors: T
authors: Zeng
authors: Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China.
authors: Yi
authors: Y
authors: Jin
authors: Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China. Electronic address: kalantes@163.com.
authors: Liang
authors: L
authors: Gao
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: Glioma; Invasion; Mutant IDH1-R132H; Proliferation; β-Catenin