RUNX3 interacts with MYCN and facilitates protein degradation in neuroblastoma
RUNX3 interacts with MYCN and facilitates protein degradation in neuroblastoma
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DOI：
10.1038/onc.2013.221
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发表时间：
2014-05
期刊：
影响因子：
8
通讯作者：
F. Yu;W. Gao;T. Yokochi;Yusuke Suenaga;K. Ando;M. Ohira;Yohko Nakamura;Akira Nakagawara
中科院分区：
文献类型：
--
作者：
F. Yu;W. Gao;T. Yokochi;Yusuke Suenaga;K. Ando;M. Ohira;Yohko Nakamura;Akira Nakagawara
RUNX3是一种与侏儒相关的转录因子，在背根神经节神经发生中起着至关重要的作用。最近的研究表明，RUNX3在胃癌、结肠癌和乳腺癌中起肿瘤抑制剂的作用。然而，RUNX3在神经母细胞瘤中的生物学作用仍然难以捉摸。在这里，我们报道了高水平的RUNX3表达有助于神经母细胞瘤患者的良好预后，而低水平的RUNX3表达导致预后不良。基于阵列的分析表明，染色体1p36的等位基因丢失是晚期神经母细胞瘤中RUNX3表达下调的原因之一。有趣的是，几名患者从MYCN和RUNX3的高mRNA表达的神经母细胞瘤中存活下来，这表明RUNX3的高表达可能会克服MYCN的侵袭行为。RUNX3的外源性表达强烈抑制神经母细胞瘤细胞系中的细胞增殖和迁移。此外，RUNX3降低MYCN扩增的神经母细胞瘤细胞系中MYCN蛋白的稳定性，并且这种RUNX3介导的MYCN降解可能取决于RUNX3和MYCN之间的物理相互作用。因此，我们的发现提供了一种肿瘤抑制机制，RUNX3通过该机制抑制神经母细胞瘤中的MYCN活性。
RUNX3, a runt-related transcription factor, has a crucial role in dorsal root ganglion neurogenesis. Recent studies have suggested that RUNX3 acts as a tumor suppressor in stomach, colon and breast cancer. However, the biological role of RUNX3 in neuroblastoma remains elusive. Here we report that high levels of RUNX3 expression contribute to the favorable outcome in patients with neuroblastoma, whereas low levels of RUNX3 expression result in poor outcome. Array-based analysis suggested that the allelic loss at chromosome 1p36 is one of the reasons why expression of RUNX3 is downregulated in advanced neuroblastomas. Interestingly, the several patients survived from neuroblastoma with both high mRNA expressions of MYCN and RUNX3, suggesting that RUNX3 high expression might overcome the aggressive behavior of MYCN. Exogenous expression of RUNX3 strongly inhibits cell proliferation and migration in neuroblastoma cell lines. Furthermore, RUNX3 reduces the stability of MYCN protein in MYCN-amplified neuroblastoma cell lines, and this RUNX3-mediated MYCN degradation may depend on the physical interaction between RUNX3 and MYCN. Thus, our findings provide a tumor-suppressing mechanism by which RUNX3 inhibits the MYCN activity in neuroblastoma.