Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma.
Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma.
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DOI：
10.1186/s40478-014-0134-6
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发表时间：
2014-10-21
影响因子：
7.1
通讯作者：
Becher OJ
中科院分区：
文献类型：
--
作者：
Misuraca KL;Barton KL;Chung A;Diaz AK;Conway SJ;Corcoran DL;Baker SJ;Becher OJ
高级别脑干胶质瘤（BSG），也称为弥漫性内在脑桥胶质瘤（DIPG），是一种无法治愈的儿科脑癌。越来越多的证据支持胶质瘤发生存在区域差异，因此BSG被认为是与大脑皮层胶质瘤（CG）不同的疾病。为了阐明BSG的独特特征，我们对巢蛋白祖细胞中启动的小鼠PDGF-B驱动的BSG和CG进行了表达分析，并确定了脑干胶质瘤发生过程特异性表达变化的简短列表，包括配对框3（Pax 3）的异常上调。在新生小鼠脑中，Pax 3表达标志着脑干祖细胞的一个子集，而它在大脑皮层中不存在，反映了其在胶质瘤中的区域表达。在体外正常脑干祖细胞中异位表达Pax 3表明Pax 3抑制凋亡。然而，Pax 3诱导的细胞凋亡抑制是p53依赖性的，并且在p53不存在的情况下，Pax 3促进脑干祖细胞的增殖。在体内，Pax 3通过以区域特异性方式缩短肿瘤潜伏期和增加肿瘤转移率和分级来增强PDGF-B驱动的胶质瘤发生，而Pax 3功能的丧失使PDGF-B驱动的、p53缺陷的BSG荷瘤小鼠的生存期延长33%。重要的是，Pax 3也在人脑胶质瘤中区域性表达，40%的人BSG具有高PAX 3 mRNA特征，揭示了与PDGFRA改变、细胞周期调控基因扩增显著相关的肿瘤子集，并且不包括ACVR 1突变。总的来说，这些数据表明，区域Pax 3表达不仅标志着一个新的子集BSG，但也有助于PDGF-B诱导的脑干胶质瘤。本文的在线版本（doi：10.1186/s40478-014-0134-6）包含补充材料，可供授权用户使用。
High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis. The online version of this article (doi:10.1186/s40478-014-0134-6) contains supplementary material, which is available to authorized users.
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DOI：
10.1097/pas.0b013e318294e817
发表时间：
2013-09
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Ballester LY;Wang Z;Shandilya S;Miettinen M;Burger PC;Eberhart CG;Rodriguez FJ;Raabe E;Nazarian J;Warren K;Quezado MM
通讯作者：
Quezado MM
在遗传学和组织学精确的脑干神经胶质瘤模型中，辐射和perifosine的临床前评估。
影响因子：
11.2
作者：
Becher OJ;Hambardzumyan D;Walker TR;Helmy K;Nazarian J;Albrecht S;Hiner RL;Gall S;Huse JT;Jabado N;MacDonald TJ;Holland EC
通讯作者：
Holland EC
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
10.5
作者：
Dai, C;Celestino, JC;Holland, EC
通讯作者：
Holland, EC
影响因子：
3.1
作者：
Chen, Jian;Xia, Liang;Shi, Wei
通讯作者：
Shi, Wei