Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma.
Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma.
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DOI：
10.1186/1471-2407-10-614
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发表时间：
2010-11-08
期刊：
影响因子：
3.8
通讯作者：
Castresana JS
中科院分区：
文献类型：
--
作者：
Shahi MH;Afzal M;Sinha S;Eberhart CG;Rey JA;Fan X;Castresana JS
Sonic hedgehog（Shh）信号通路对细胞生长和分化至关重要。这一途径的损伤可能导致出生缺陷和癌症。尽管其在癌症发展中的重要性，但Shh通路在脑肿瘤的肿瘤发生中尚未得到彻底研究。在这项研究中，我们试图了解GLI 1的调节作用，直接下游激活Shh信号通路的下游靶基因PTCH 1，细胞周期蛋白D2，斑珠蛋白，NKX2.2和PAX 6在髓母细胞瘤和星形细胞肿瘤。我们沉默GLI 1表达髓母细胞瘤和星形胶质细胞系转染siRNA对GLI 1。随后，我们进行了RT-PCR和定量真实的时间RT-PCR（qRT-PCR）来检测下游靶基因PTCH 1、Cyclin D2、Plakoglobin、NKX 2. 2和PAX 6的表达。我们还试图在14个细胞系和41个原发性髓母细胞瘤和星形细胞瘤肿瘤样本中关联GLI 1及其调控基因的表达模式。我们还评估了这14个细胞系和58个原发性肿瘤样本中细胞周期蛋白D2和PTCH 1启动子的甲基化状态。GLI 1的沉默表达导致髓母细胞瘤细胞系中所有靶基因的上调，而星形细胞瘤中仅PTCH 1上调。我们还观察到大量星形细胞瘤细胞系（63%）和原发性星形细胞瘤肿瘤样本（32%）中细胞周期蛋白D2启动子的甲基化，但在任何髓母细胞瘤样本中均未观察到甲基化。PTCH 1启动子甲基化在星形细胞瘤中的发生率低于Cyclin D2启动子甲基化，而在髓母细胞瘤中则完全没有。我们的研究结果表明Shh-GLI 1信号的不同调节机制。这些差异根据受影响的下游靶基因、组织的起源以及这些基因中的一些的表观遗传调控而变化。
The Sonic hedgehog (Shh) signaling pathway is critical for cell growth and differentiation. Impairment of this pathway can result in both birth defects and cancer. Despite its importance in cancer development, the Shh pathway has not been thoroughly investigated in tumorigenesis of brain tumors. In this study, we sought to understand the regulatory roles of GLI1, the immediate downstream activator of the Shh signaling pathway on its downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6 in medulloblastoma and astrocytic tumors. We silenced GLI1 expression in medulloblastoma and astrocytic cell lines by transfection of siRNA against GLI1. Subsequently, we performed RT-PCR and quantitative real time RT-PCR (qRT-PCR) to assay the expression of downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6. We also attempted to correlate the pattern of expression of GLI1 and its regulated genes in 14 cell lines and 41 primary medulloblastoma and astrocytoma tumor samples. We also assessed the methylation status of the Cyclin D2 and PTCH1 promoters in these 14 cell lines and 58 primary tumor samples. Silencing expression of GLI1 resulted up-regulation of all target genes in the medulloblastoma cell line, while only PTCH1 was up-regulated in astrocytoma. We also observed methylation of the cyclin D2 promoter in a significant number of astrocytoma cell lines (63%) and primary astrocytoma tumor samples (32%), but not at all in any medulloblastoma samples. PTCH1 promoter methylation was less frequently observed than Cyclin D2 promoter methylation in astrocytomas, and not at all in medulloblastomas. Our results demonstrate different regulatory mechanisms of Shh-GLI1 signaling. These differences vary according to the downstream target gene affected, the origin of the tissue, as well as epigenetic regulation of some of these genes.
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