Identification of FoxR2 as an Oncogene in Medulloblastoma
Identification of FoxR2 as an Oncogene in Medulloblastoma
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DOI：
10.1158/0008-5472.can-13-1523
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发表时间：
2014-04-15
期刊：
影响因子：
11.2
通讯作者：
Watanabe, Sumiko
中科院分区：
文献类型：
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作者：
Koso, Hideto;Tsuhako, Asano;Watanabe, Sumiko
髓母细胞瘤是最常见的儿科脑肿瘤，并且在类似于25%的病例中，其由颗粒神经元前体（GNP）细胞中的Sonic Hedgehog（SHH）通路的异常激活驱动。在这项研究中，我们确定了新的髓母细胞瘤驱动基因，通过转座子诱变筛选野生型和Trp 53突变小鼠的大脑发育。沿着确定的驱动基因，如Gli 1和Crebbp的26个候选人被确定。转录因子FoxR 2是筛选中最常见的基因，在SHH亚型的一小部分人髓母细胞瘤中过表达。Tgif 2和Alx 4是在筛选中发现的两个新的推定癌基因，在人髓母细胞瘤SHH亚型中强表达。这两个基因的突变与Gli 1的突变相互排斥，并且倾向于共同发生，与SHH通路的参与一致。值得注意的是，Foxr 2，Tgif 2和Alx 4与Gli 1合作激活Gli-binding位点，加强了它们在SHH信号传导中发挥作用的证据。为了支持致癌功能，Foxr 2过表达转化了NIH 3 T3细胞并促进了GNP的增殖，后者也在Tgif 2和Alx 4中观察到。这些发现提供了将Foxr 2、Tgif 2和Alx 4与SHH亚型髓母细胞瘤相关联的遗传和功能证据。(C)2014年AACR。
Medulloblastoma is the most common pediatric brain tumor, and in similar to 25% of cases, it is driven by aberrant activation of the Sonic Hedgehog (SHH) pathway in granule neuron precursor (GNP) cells. In this study, we identified novel medulloblastoma driver genes through a transposon mutagenesis screen in the developing brain of wild-type and Trp53 mutant mice. Twenty-six candidates were identified along with established driver genes such as Gli1 and Crebbp. The transcription factor FoxR2, the most frequent gene identified in the screen, is overexpressed in a small subset of human medulloblastoma of the SHH subtype. Tgif2 and Alx4, 2 new putative oncogenes identified in the screen, are strongly expressed in the SHH subtype of human medulloblastoma. Mutations in these two genes were mutually exclusive with mutations in Gli1 and tended to cooccur, consistent with involvement in the SHH pathway. Notably, Foxr2, Tgif2, and Alx4 activated Gli-binding sites in cooperation with Gli1, strengthening evidence that they function in SHH signaling. In support of an oncogenic function, Foxr2 overexpression transformed NIH3T3 cells and promoted proliferation of GNPs, the latter of which was also observed for Tgif2 and Alx4. These findings offer forward genetic and functional evidence associating Foxr2, Tgif2, and Alx4 with SHH subtype medulloblastoma. (C) 2014 AACR.