Dickkopf-1 is down-regulated by MYCN and inhibits neuroblastoma cell proliferation
Dickkopf-1 is down-regulated by MYCN and inhibits neuroblastoma cell proliferation
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DOI：
10.1016/j.canlet.2007.06.011
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发表时间：
2007-10-28
期刊：
影响因子：
9.7
通讯作者：
Valentijn, Linda J.
中科院分区：
文献类型：
--
作者：
Koppen, Arjen;Ait-Aissa, Rachida;Valentijn, Linda J.
神经母细胞瘤是发育中的周围交感神经系统的肿瘤，起源于神经嵴。 20% 的神经母细胞瘤显示 MYCN 癌基因扩增，这与不良预后相关。 MYCN转录因子可以激活和抑制基因表达。为了拓宽我们对 MYCN 下调基因谱的了解，我们生成了神经母细胞瘤细胞系 SHEP-21N 和 SKNAS-NmycER 的基因表达谱，其中 MYCN 活性可以受到调节。在这项研究中，我们表明MYCN抑制两种细胞系中Dickkopf-1(DKK1)的表达。 DKK1是wnt/β-连环蛋白信号级联的有效抑制剂，已知其在神经嵴细胞迁移中起作用。我们产生了DKK1诱导型细胞系IMR32-DKK I，其在DKK1表达后显示出增殖受损。令人惊讶的是，DKK1表达不抑制典型的wnt/β-连环蛋白信号传导，表明DKK1在wnt途径的替代途径中的作用。两个1MR32DKK1克隆的基因表达谱显示，只有少数基因，其中SYNPO2，被DKK1上调。 SYNPO2 编码肌动蛋白结合蛋白，之前发现它可以抑制前列腺癌细胞的增殖和侵袭。这些结果表明MYCN可能通过抑制DKK1的表达来刺激细胞增殖。 DKK1可能通过诱导SYNPO2表达来发挥其部分生长抑制作用。 (C) 2007 Elsevier Ireland Ltd. 保留所有权利。
Neuroblastomas are tumors of the developing peripheral sympathetic nervous system, which originates from the neural crest. Twenty percent of neuroblastomas show amplification of the MYCN oncogene, which correlates with poor prognosis. The MYCN transcription factor can activate and repress gene expression. To broaden our insight in the spectrum of Genes down -regulated by MYCN, we Generated gene expression profiles of the neuroblastoma cell lines SHEP-21N and SKNAS-NmycER, in which MYCN activity can be regulated. In this study, we show that MYCN suppresses the expression of Dickkopf-l (DKKl) in both cell lines. DKKl is a potent inhibitor of the wnt/beta-catenin signalling cascade, which is known to function in neural crest cell migration. We generated a DKKl inducible cell line, IMR32-DKK I, which showed impaired proliferation upon DKK l expression. Surprisingly, DKKl expression did not inhibit the canonical wnt/beta-catenin signalling, suggesting a role of DKKl in an alternative route of the wnt pathway. Gene expression profiling of two 1MR32DKKl clones showed that only a few genes, amongst which SYNPO2, were up-regulated by DKKl. SYNPO2 encodes an actin-binding protein and was previously found to inhibit proliferation and invasiveness of prostate cancer cells. These results Suggest that MYCN might stimulate cell proliferation by inhibiting the expression of DKKl. DKKl might exert part of its growth suppressive effect by induction of SYNPO2 expression. (C) 2007 Elsevier Ireland Ltd. All rights reserved.