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在携带异柠檬酸脱氢酶1（IDH1）R132H突变的人类胶质瘤中，微小RNA-148a通过下调生长停滞和DNA损伤诱导蛋白45A（GADD45A）来增加胶质瘤细胞的迁移和侵袭能力。

MiR-148a increases glioma cell migration and invasion by downregulating GADD45A in human gliomas with IDH1 R132H mutations.

作者信息

Cui Daming, Sajan Pandey, Shi Jinlong, Shen Yiwen, Wang Ke, Deng Xianyu, Zhou Lin, Hu Pingping, Gao Liang

机构信息

Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China.

Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, People's Republic of China.

出版信息

Oncotarget. 2017 Apr 11;8(15):25345-25361. doi: 10.18632/oncotarget.15867.

DOI:10.18632/oncotarget.15867
PMID:28445981
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5421935/
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.

摘要

高级别胶质瘤是预后较差的严重肿瘤。异柠檬酸脱氢酶（IDH1）基因中的R132H突变可延长胶质瘤患者的生存期。在本研究中，我们调查了哪些基因在IDH1野生型（IDH1WT）或IDH1 R132H突变（IDH1R132H）胶质母细胞瘤细胞中受到差异调节。在IDH1R132H人胶质母细胞瘤组织中，生长停滞和DNA损伤诱导蛋白（GADD45A）下调，而微小RNA 148a（miR-148a）上调。GADD45A与miR-148a之间的关系尚不清楚。体外实验表明，GADD45A负向调节IDH1R132H胶质瘤细胞的增殖、迁移和侵袭，以及IDH1R132H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表明，GADD45A在体内可降低肿瘤发生。我们的研究结果表明，miR-148a通过下调GADD45A促进胶质瘤细胞侵袭和肿瘤发生。我们的研究结果为IDH1R132H胶质瘤中miR-148a如何下调GADD45A提供了新的见解，并可能有助于确定有效治疗高级别胶质瘤的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6522/5421935/51c03380cddb/oncotarget-08-25345-g011.jpg
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