Abstract
High-grade gliomas are severe tumors with poor prognosis. An R132H mutation in the isocitrate dehydrogenase (IDH1) gene prolongs the life of glioma patients. In this study, we investigated which genes are differentially regulated in IDH1 wild type (IDH1WT) or IDH1 R132H mutation (IDH1R132H) glioblastoma cells. Growth arrest and DNA-damage-inducible protein (GADD45A) was downregulated and microRNA 148a (miR-148a) was upregulated in in IDH1R132H human glioblastomas tissues. The relationship between GADD45A and miR-148a is unknown. In vitro experiments showed that GADD45A negatively regulates IDH1R132H glioma cell proliferation, migration, and invasion, and neurosphere formation in IDH1R132H glioblastoma stem cells (GSC). In addition, a human orthotopic xenograft mouse model showed that GADD45A reduced tumorigenesis in vivo. Our findings demonstrated that miR-148a promotes glioma cell invasion and tumorigenesis by downregulating GADD45A. Our findings provide novel insights into how GADD45A is downregulated by miR-148a in IDH1R132H glioma and may help to identify therapeutic targets for the effective treatment of high-grade glioma.
Highlights
Gliomas are the most prevalent primary brain tumors and are highly aggressive and malignant [1]
Our findings provide novel insights into how GADD45A is downregulated by miR-148a in IDH1R132H glioma and may help to identify therapeutic targets for the effective treatment of high-grade glioma
To investigate which genes are differentially expressed in IDH1 wild type (IDH1WT) and IDH1R132H glioma cells, we performed microarray analysis (Supplementary Figure 1)
Summary
Gliomas are the most prevalent primary brain tumors and are highly aggressive and malignant [1]. The R132H mutation (IDH1R132H) is the most common [7, 8] This mutation significantly improves the prognosis of patients with glioblastoma [9]. We recently showed that the IDH1 R132H mutation reduces the proliferation and invasion of human glioblastoma cells, indicating a tumor suppressor function. These effects were mediated by negatively regulating β-catenin signaling [10]. Wnt/β-catenin signaling is mediated by microRNAs (miRNAs), which regulate cancer-related genes They have been used to classify [11] and detect [12] different cancers, and may represent therapeutic targets through oncogenic and tumor suppressor functions [13, 14]
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