MiR-148a increases glioma cell migration and invasion by downregulating GADD45A in human gliomas with IDH1 R132H mutations.
MiR-148a increases glioma cell migration and invasion by downregulating GADD45A in human gliomas with IDH1 R132H mutations.
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DOI：
10.18632/oncotarget.15867
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发表时间：
2017-04-11
期刊：
影响因子：
--
通讯作者：
Gao L
中科院分区：
文献类型：
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作者：
Cui D;Sajan P;Shi J;Shen Y;Wang K;Deng X;Zhou L;Hu P;Gao L
高级别胶质瘤是预后差的严重肿瘤。异柠檬酸脱氢酶（IDH 1）基因R132 H突变延长胶质瘤患者的生命。在这项研究中，我们研究了哪些基因在IDH 1野生型（IDH 1 WT）或IDH 1 R132 H突变（IDH 1 R132 H）胶质母细胞瘤细胞中受到差异调节。在IDH 1 R132 H人胶质母细胞瘤组织中，生长停滞和DNA损伤诱导蛋白（GADD 45 A）下调，microRNA 148 a（miR-148 a）上调。GADD 45 A和miR-148 a之间的关系尚不清楚。体外实验表明，GADD 45 A负调控IDH 1 R132 H胶质瘤细胞增殖、迁移和侵袭，以及IDH 1 R132 H胶质母细胞瘤干细胞（GSC）中的神经球形成。此外，人原位异种移植小鼠模型显示GADD 45 A减少体内肿瘤发生。我们的研究结果表明，miR-148 a通过下调GADD 45 A促进胶质瘤细胞的侵袭和肿瘤发生。我们的研究结果提供了新的见解，GADD 45 A是如何在IDH 1 R132 H胶质瘤中被miR-148 a下调的，并可能有助于确定有效治疗高级别胶质瘤的治疗靶点。
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.