PPM1D is a potential target for 17q gain in neuroblastoma.
PPM1D is a potential target for 17q gain in neuroblastoma.
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发表时间：
2003-04
期刊：
影响因子：
11.2
通讯作者：
F. Saito-Ohara;I. Imoto;J. Inoue;H. Hosoi;A. Nakagawara;T. Sugimoto;J. Inazawa
中科院分区：
文献类型：
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作者：
F. Saito-Ohara;I. Imoto;J. Inoue;H. Hosoi;A. Nakagawara;T. Sugimoto;J. Inazawa
神经母细胞瘤（NBs）表现出复杂的遗传异常模式，可能包括MYCN基因扩增、1p缺失或17q DNA增加，后者是NB肿瘤中最常见的观察结果。然而，对NB发生和发展的特定基因和分子机制仍然知之甚少。我们利用比较基因组杂交技术研究了25个NB细胞系的DNA拷贝数畸变，并在17q23处发现了最小的共同增益区。尽管远端17q的增加是目前NB患者不良预后最有效的遗传预测因子，但到目前为止，尚未报道该区域的潜在靶基因。因此，我们详细定义了17q23扩增子，并测定了在NB细胞系中观察到的最小重叠区域内的15个基因的表达水平，以确定最可能的靶基因。其中，有7个基因（CLTC、VMP1、delta-tubulin、RPS6KB1、FLJ22087、APPBP2、PPM1D）通过区域拷贝数的增加而持续过表达。分析这7个基因在32例原发性NB肿瘤中的表达水平发现，仅在PPM1D中，高表达与较差的临床预后之间存在显著相关性。此外，通过转染反义寡核苷酸下调PPM1D在很大程度上抑制了NB细胞系的生长，至少部分原因是参与了导致凋亡细胞死亡的过程。综上所述，我们的研究结果表明PPM1D是NB肿瘤中最可能的17q23获得/扩增的靶标，并且可能在该疾病的发病机制中发挥重要作用。
Neuroblastomas (NBs) show complex patterns of genetic abnormalities, which may include amplification of the MYCN gene, deletion of 1p, or a gain of DNA at 17q, the last being the most frequent observation in NB tumors. However, the specific genes and the molecular mechanisms responsible for development and progression of NB remain poorly understood. We investigated aberrations of DNA copy number in 25 NB cell lines using comparative genomic hybridization and identified a minimal common region of gain at 17q23. Although gain of distal 17q is the most powerful genetic predictor of adverse outcome currently available for patients with NB, thus far, no potential target genes have been reported for that region. Therefore, we defined the 17q23 amplicon in detail and determined expression levels of 15 genes located within the smallest region of overlap observed among our NB cell lines to identify the most likely target gene(s). Among them, seven (CLTC, VMP1, delta-tubulin, RPS6KB1, FLJ22087, APPBP2, and PPM1D) were consistently overexpressed through increases in regional copy number. Analysis of expression levels of those seven genes in 32 primary NB tumors revealed a significant correlation between higher expression and poorer clinical outcome only with respect to PPM1D. Moreover, down-regulation of PPM1D by transfection of an antisense oligonucleotide suppressed the growth of NB cell lines to a remarkable degree, at least partly by participating in a process leading to apoptotic cell death. Taken together, our results indicate that PPM1D is the most likely target of the 17q23 gain/amplification in NB tumors and may have an important role in the pathogenesis of this disease.