APOBEC3G acts as a therapeutic target in mesenchymal gliomas by sensitizing cells to radiation-induced cell death.
APOBEC3G acts as a therapeutic target in mesenchymal gliomas by sensitizing cells to radiation-induced cell death.
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DOI：
10.18632/oncotarget.17348
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发表时间：
2017-08-15
期刊：
影响因子：
--
通讯作者：
Alfred Yung WK
中科院分区：
文献类型：
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作者：
Wang Y;Wu S;Zheng S;Wang S;Wali A;Ezhilarasan R;Sulman EP;Koul D;Alfred Yung WK
脑肿瘤的基因组、转录和蛋白质组学分析表明，脑肿瘤亚型在其途径活性、进展和对治疗的反应方面存在差异。我们对胶质瘤起始细胞（Glioma initiation Cells, GICs）进行了表达谱分析，不同GICs组之间的比较分析显示了基因表达的主要差异。分层聚类分析揭示了GICs的异质性，在一些主要的间充质表型调控基因中，我们发现ABOBEC3G是间充质组中最具鉴别性的基因之一。ABOBEC3G显示与TCGA GBM患者队列的总生存率有很强的相关性。APOBEC3G调控细胞侵袭，在GICs中，该基因的沉默抑制细胞侵袭和胶质瘤球的起始。APOBEC3G通过调控Smad2靶基因血栓反应蛋白1、基质金属肽酶2和TIMP金属肽酶抑制剂1，通过TGFβ/Smad2途径调控侵袭。我们还发现，靶向APOBEC3G可以通过减弱DNA修复途径的激活，使癌细胞对辐射诱导的细胞死亡敏感。这种反应主要表现为pChk2在APOBEC3G基因敲低细胞中的表达降低。综上所述，我们发现APOBEC3G基因是一个间充质富集基因，它控制着APOBEC3G的侵袭和敲低，使细胞对辐射诱导的细胞死亡敏感，这表明APOBEC3G可以被考虑用于GBM患者的预后分层。
Genomic, transcriptional, and proteomic analyses of brain tumors reveal that subtypes differ in their pathway activity, progression, and response to therapy. We performed an expression profiling of Glioma Initiating Cells (GICs) and comparative analysis between different groups of GICs indicates major variations in gene expression. Hierarchical clustering analysis revealed groups of GICs reflecting their heterogeneity, and among some of the genes as major regulators of mesenchymal phenotype, we identified ABOBEC3G as one of the most discriminating genes in mesenchymal group. ABOBEC3G revealed a strong correlation with overall survival in TCGA GBM patient cohorts. APOBEC3G regulates cell invasion and silencing of this gene in GICs inhibits cell invasion and also glioma sphere initiation. APOBEC3G controls invasion through TGFβ/Smad2 pathway by regulating Smad2 target genes Thrombospondin 1, matrix metallopeptidase 2 and TIMP metallopeptidase inhibitor 1. We also show that targeting APOBEC3G can sensitize cancer cells to radiation induced cell death by attenuating activation of the DNA repair pathway. This response is mainly shown by decreased pChk2 expression in knockdown APOBEC3G cells. Taken together, we show that APOBEC3G gene is a mesenchymal enriched gene that controls invasion and knockdown of APOBEC3G sensitizes cells to radiation induced cell death, suggesting that APOBEC3G can be considered for use in stratifying patients with GBM for prognostic considerations.
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影响因子：
64.5
作者：
Harris, RS;Bishop, KN;Malim, MH
通讯作者：
Malim, MH
影响因子：
5.7
作者：
GARDEN, AS;MAOR, MH;LEE, YY
通讯作者：
LEE, YY
影响因子：
2.3
作者：
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通讯作者：
Chauhan, Nalini
影响因子：
9
作者：
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通讯作者：
Kruyt FA
影响因子：
64.8
作者：
通讯作者：
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