The miR-17∼92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma
The miR-17∼92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma
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DOI：
10.1073/pnas.0809579106
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发表时间：
2009-02-24
影响因子：
11.1
通讯作者：
Roussel, Martine F.
中科院分区：
文献类型：
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作者：
Uziel, Tamar;Karginov, Fedor V.;Roussel, Martine F.
髓母细胞瘤（MBs）是儿童最常见的脑肿瘤。一些被认为起源于小脑颗粒神经元祖细胞（GNPs），不能经历正常的细胞周期退出和分化。由于microrna调节细胞生理和发育的许多方面，我们推断miRNA表达的改变可能有助于MB的发生。我们使用2种具有特异性启动突变的自发小鼠MB模型来验证这一假设，Ink4c(-/-)；Ptch1（+/-）和Ink4c(-/-)；p53(- / -)。我们发现，无论基因型如何，相对于成熟小鼠小脑，增殖小鼠GNPs和mb中有26种miRNAs表达增加，24种miRNAs表达减少。在26个过表达的mirna中，9个是由类似于92簇家族的miR-17编码的，这是一组在几种肿瘤类型中与致癌基因有关的microrna。对人MBs的分析表明，与92簇mirna （miR-92， miR-19a和miR-20）相似的3种miR-17在具有组成性激活的Sonic Hedgehog （SHH）信号通路的人MBs中也过表达，但在其他形式的疾病中没有过表达。为了测试类似于92簇的miR-17是否能促进MB的形成，我们在出生后(P)天P6 Ink4c（-/-）的小脑分离的GNPs中强化了这些mirna的表达；Ptch1(+ / -)老鼠。这些，但不是来自Ink4c（-/-）的类似工程细胞；p53（-/-）小鼠在原位移植中形成完全外显率的MBs。有趣的是，异位表达miR-17类似于92的原位小鼠肿瘤失去了野生型Ptch1等位基因的表达。我们的研究结果表明，在小鼠和人的MBs发育过程中，类似于92簇的miR-17与SHH信号通路之间存在功能协作。
Medulloblastomas (MBs) are the most common brain tumors in children. Some are thought to originate from cerebellar granule neuron progenitors (GNPs) that fail to undergo normal cell cycle exit and differentiation. Because microRNAs regulate numerous aspects of cellular physiology and development, we reasoned that alterations in miRNA expression might contribute to MB. We tested this hypothesis using 2 spontaneous mouse MB models with specific initiating mutations, Ink4c(-/-); Ptch1(+/-) and Ink4c(-/-); p53(-/-). We found that 26 miRNAs showed increased expression and 24 miRNAs showed decreased expression in proliferating mouse GNPs and MBs relative to mature mouse cerebellum, regardless of genotype. Among the 26 overexpressed miRNAs, 9 were encoded by the miR-17 similar to 92 cluster family, a group of microRNAs implicated as oncogenes in several tumor types. Analysis of human MBs demonstrated that 3 miR-17 similar to 92 cluster miRNAs (miR-92, miR-19a, and miR-20) were also overexpressed in human MBs with a constitutively activated Sonic Hedgehog (SHH) signaling pathway, but not in other forms of the disease. To test whether the miR-17 similar to 92 cluster could promote MB formation, we enforced expression of these miRNAs in GNPs isolated from cerebella of postnatal (P) day P6 Ink4c(-/-); Ptch1(+/-) mice. These, but not similarly engineered cells from Ink4c(-/-); p53(-/-) mice, formed MBs in orthotopic transplants with complete penetrance. Interestingly, orthotopic mouse tumors ectopically expressing miR-17 similar to 92 lost expression of the wild-type Ptch1 allele. Our findings suggest a functional collaboration between the miR-17 similar to 92 cluster and the SHH signaling pathway in the development of MBs in mouse and man.