Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro-differentiative gene PC3
Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro-differentiative gene PC3
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DOI：
10.1096/fj.06-7548com
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发表时间：
2007-07-01
期刊：
影响因子：
4.8
通讯作者：
Tirone, Felice
中科院分区：
文献类型：
--
作者：
Farioli-Vecchioli, Stefano;Tanori, Mirella;Tirone, Felice
髓母细胞瘤是儿童时期最常见的脑肿瘤，起源于小脑颗粒细胞前体（GCPs），位于小脑外颗粒层（EGL）。抗增殖基因PC 3（Tis 21/BTG 2）通过诱导GCPs从增殖向分化转变来促进小脑神经发生。为了评估PC 3是否可以预防GCP的肿瘤转化和成神经管细胞瘤的发展，我们将在GCP中条件性表达PC 3的转基因小鼠（TgPC 3）与Patched 1杂合子小鼠（Ptc（+/-））杂交，Patched 1杂合子小鼠是一种成神经管细胞瘤发病机制的模型，其特征在于Sonic Hedgehog通路的过度活化。在Ptc（+/-）/TgPC 3小鼠中PC 3的围产期上调导致髓母细胞瘤发病率降低约40%，并显著减少肿瘤前异常，如增生性EGL区域和病变。此外，在Ptc（+/-）GCPs中观察到的细胞周期蛋白D1过表达、过度增殖和分化缺陷在Ptc（+/-）/TgPC 3小鼠中恢复正常。PC 3介导的细胞周期蛋白D1表达的抑制与PC 3对细胞周期蛋白D1启动子的募集相关，这伴随着组蛋白去乙酰化。值得注意的是，在癌前病变以及人和鼠髓母细胞瘤中观察到PC 3的下调。总的来说，这表明PC 3可以通过控制细胞周期和促进GCP的分化来防止髓母细胞瘤的发展。法里奥利-韦基奥利，S.，Tanori，M.，米舍利湖，加-地Mancuso，M.，莱昂纳尔迪湖萨兰，Ciotti，M. T.，Ferretti，E.，Gulino，A.，Pazzaglia，S.，Tirone，F.抗增殖和促分化基因PC 3对髓母细胞瘤肿瘤发生的抑制作用
Medulloblastoma, the most common brain tumor in childhood, appears to originate from cerebellar granule cell precursors (GCPs), located in the external granular layer (EGL) of the cerebellum. The antiproliferative gene PC3 (Tis21/BTG2) promotes cerebellar neurogenesis by inducing GCPs to shift from proliferation to differentiation. To assess whether PC3 can prevent the neoplastic transformation of GCPs and medulloblastoma development, we crossed transgenic mice conditionally expressing PC3 (TgPC3) in GCPs with Patched1 heterozygous mice (Ptc(+/-)), a model of medulloblastoma pathogenesis characterized by hyperactivation of the Sonic Hedgehog pathway. Perinatal up-regulation of PC3 in Ptc(+/-)/TgPC3 mice results in a decrease of medulloblastoma incidence of similar to 40% and in a marked reduction of preneoplastic abnormalities, such as hyperplastic EGL areas and lesions. Moreover, overexpression of cyclin D1, hyperproliferation, and defective differentiation-observed in Ptc(+/-) GCPs-are restored to normality in Ptc(+/-)/TgPC3 mice. The PC3-mediated inhibition of cyclin D1 expression correlates with recruitment of PC3 to the cyclin D1 promoter, which is accompanied by histone deacetylation. Remarkably, down-regulation of PC3 is observed in preneoplastic lesions, as well as in human and murine medulloblastomas. As a whole, this indicates that PC3 may prevent medulloblastoma development by controlling cell cycle and promoting differentiation of GCPs.-Farioli-Vecchioli, S., Tanori, M., Micheli, L., Mancuso, M., Leonardi, L., Saran, A., Ciotti, M. T., Ferretti, E., Gulino, A., Pazzaglia, S., Tirone, F. Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro-differentiative gene PC3.