Nr4a3, a possibile oncogenic factor for neuroblastoma associated with CpGi methylation within the third exon.
Nr4a3, a possibile oncogenic factor for neuroblastoma associated with CpGi methylation within the third exon.
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DOI：
10.3892/ijo.2014.2340
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发表时间：
2014-05
影响因子：
5.2
通讯作者：
Nagase H
中科院分区：
文献类型：
--
作者：
Uekusa S;Kawashima H;Sugito K;Yoshizawa S;Shinojima Y;Igarashi J;Ghosh S;Wang X;Fujiwara K;Ikeda T;Koshinaga T;Soma M;Nagase H
Nr4a3外显子3 CpG岛（CpG i）的异常甲基化最初在多步骤小鼠皮肤癌发生过程中被发现。Nr4a3也被认为是神经元发育的关键基因。因此，我们检测了来自15天胚胎、新生儿和12周龄成人的小鼠脑组织中的Nr4a3外显子3 CpGi甲基化，发现其甲基化和Nr4a3表达在出生后的小鼠脑发育过程中显著增加。此外，在神经母细胞瘤标本中，人类基因组中的同源区域频繁且异常地甲基化。DNA甲基化的定量分析显示，低甲基化的CpG岛NR4A3外显子3，但不是外显子1被确定在三个神经母细胞瘤相比，匹配的肾上腺。对20名神经母细胞瘤患者进行了额外的分析，20名患者中有8名显示NR4A3外显子3上的CpG i低甲基化。这8例患者的生存率明显低于高甲基化患者。与正常组织相比，NR4A3在神经母细胞瘤组织中的免疫组化表达通常较弱。此外，MYCN扩增的NB9细胞系显示低甲基化和低表达NR4A3，而非MYCN扩增的NB69细胞系显示高甲基化和高表达。这些结果表明，NR4A3外显子3处CpGi的DNA低甲基化与NR4A3的低表达相关，并且与神经母细胞瘤的不良预后相关。由于NR4A3的上调与小鼠中的高甲基化和神经元分化相关，因此与NR4A3低表达相关的神经母细胞瘤的不良预后可能部分由其分化失调来解释。
Aberrant methylation of Nr4a3 exon 3 CpG island (CpGi) was initially identified during multistep mouse skin carcinogenesis. Nr4a3 is also known as a critical gene for neuronal development. Thus, we examined the Nr4a3 exon 3 CpGi methylation in mouse brain tissues from 15-day embryos, newborns and 12-week-old adults and found significant increase of its methylation and Nr4a3 expression during mouse brain development after birth. In addition, homologous region in human genome was frequently and aberrantly methylated in neuroblastoma specimens. A quantitative analysis of DNA methylation revealed that hypomethylation of CpG islands on NR4A3 exon 3, but not on exon 1 was identified in three neuroblastomas compared with matched adrenal glands. Additional analysis for 20 neuroblastoma patients was performed and 8 of 20 showed hypomethylation of the CpGi on NR4A3 exon 3. The survival rate of those 8 patients was significantly lower compared with those in patients with hypermethylation. Immunohistochemical NR4A3 expression was generally faint in neuroblastoma tissues compared with normal tissues. Moreover, the MYCN amplified NB9 cell line showed hypomethylation and low expression of NR4A3, while the non-MYCN amplified NB69 cell line showed hypermethylation and high expression. These results indicate that DNA hypomethylation of the CpGi at NR4A3 exon 3 is associated with low NR4A3 expression, and correlates with poor prognosis of neuroblastoma. Since NR4A3 upregulation associated with the hypermethylation and neuronal differentiation in mice, poor prognosis of neuroblastoma associated with NR4A3 low expression may be partly explained by dysregulation of its differentiation.
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