Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma
Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma
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DOI：
10.1038/sj.onc.1208865
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发表时间：
2005-10-27
期刊：
影响因子：
8
通讯作者：
Rao, MRS
中科院分区：
文献类型：
--
作者：
Somasundaram, K;Reddy, SP;Rao, MRS
星形细胞瘤是最常见的脑癌类型，占所有脑肿瘤的一半以上。为了鉴定描述星形细胞瘤进展的标记物，我们使用含有 1152 个癌症特异性基因的 cDNA 微阵列对不同级别的星形细胞瘤样本进行了微阵列分析。数据分析确定了正常脑组织和星形细胞瘤之间以及 II/III 级星形细胞瘤和多形性胶质母细胞瘤（GBM；IV 级）之间的几个差异调节基因。我们发现了几个已知与恶性肿瘤有关的基因，包括 Achaetescute 复合体样 1（果蝇）（ASCL1；哈希 1）。由于 ASCL 与神经内分泌癌、甲状腺髓样癌和小细胞肺癌有关，因此我们选择检查 ASCL1 在星形细胞瘤发展中的作用。我们的数据显示，ASCL1 在进行性星形细胞瘤中过度表达，如 85.71% (6/7) 的 II 级弥漫性星形细胞瘤 (DA)、90% (9/10) 的 III 级间变性星形细胞瘤 (AA) 和 87.5% (7/8) 的继发性 GBM 中 ASCL1 转录水平升高所证明，而大多数原发性新生 GBM 的表达与正常脑水平相似或低于正常水平（66.67%；8/12）。进行性星形细胞瘤中ASCL1的上调伴随着Notch信号传导的抑制，如未诱导的HES1水平（Notch1的转录靶标）、HES6水平的增加（HES1介导的ASCL1抑制的显性失活抑制剂）以及Notch配体Delta1水平的增加（能够通过形成细胞内Notch配体自主复合物来抑制Notch信号传导）。我们的结果表明，Notch 信号传导的抑制可能是 II 级 DA 发展以及随后进展为 III 级 AA 和继发性 GBM 的重要早期事件。此外，ASCL1 似乎是区分原发性 GBM 和继发性 GBM 的假定标记。
Astrocytoma is the most common type of brain cancer constituting more than half of all brain tumors. With an aim to identify markers describing astrocytoma progression, we have carried out microarray analysis of astrocytoma samples of different grades using cDNA microarray containing 1152 cancer-specific genes. Data analysis identified several differentially regulated genes between normal brain tissue and astrocytoma as well as between grades II/III astrocytoma and glioblastoma multiforme (GBM; grade IV). We found several genes known to be involved in malignancy including Achaetescute complex-like 1(Drosophila) (ASCL1; Hash 1). As ASCL has been implicated in neuroendocrine, medullary thyroid and small-cell lung cancers, we chose to examine the role of ASCL1 in the astrocytoma development. Our data revealed that ASCL1 is overexpressed in progressive astrocytoma as evidenced by increased levels of ASCL1 transcripts in 85.71% (6/7) of grade II diffuse astrocytoma (DA), 90% (9/10) of grade III anaplastic astrocytoma (AA) and 87.5% (7/8) of secondary GBMs, while the majority of primary de novo GBMs expressed similar to or less than normal brain levels (66.67%; 8/12). ASCL1 upregulation in progressive astrocytoma is accompanied by inhibition of Notch signaling as seen by uninduced levels of HES1, a transcriptional target of Notch1, increased levels of HES6, a dominant-negative inhibitor of HES1-mediated repression of ASCL1, and increased levels of Notch ligand Delta1, which is capable of inhibiting Notch signaling by forming intracellular Notch ligand autonomous complexes. Our results imply that inhibition of Notch signaling may be an important early event in the development of grade II DA and subsequent progression to grade III AA and secondary GBM. Furthermore, ASCL1 appears to be a putative marker to distinguish primary GBM from secondary GBM.