PDCD4 gene silencing in gliomas is associated with 5'CpG island methylation and unfavourable prognosis.
PDCD4 gene silencing in gliomas is associated with 5'CpG island methylation and unfavourable prognosis.
复制标题
DOI：
10.1111/j.1582-4934.2008.00497.x
复制
发表时间：
2009-10
影响因子：
5.3
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Gao F;Wang X;Zhu F;Wang Q;Zhang X;Guo C;Zhou C;Ma C;Sun W;Zhang Y;Chen YH;Zhang L
程序性细胞死亡4(PDCD4)是一种新近发现的肿瘤抑制因子，它通过抑制基因转录和翻译来抑制肿瘤的发生。在几种类型的人类癌症中都发现了PDCD4表达的缺失，包括最常见的脑癌--胶质瘤。然而，肿瘤细胞中PDCD4基因沉默的分子机制尚不清楚。在这里，我们报告了5‘CpG岛甲基化是脑胶质瘤中PDCD4mRNA沉默的主要原因。47%(14/30)的胶质瘤组织中存在PDCD45‘CpG岛甲基化，这种甲基化与PDCD4mRNA表达缺失显著相关(γ=−1.000，P<；0.0001)。用DNA甲基转移酶抑制剂5-氮杂-2‘-脱氧胞苷阻断胶质瘤细胞的甲基化，恢复了PDCD4基因的表达，抑制了细胞的增殖，降低了细胞的克隆形成能力。对84例胶质瘤患者进行的纵向研究表明，高级别肿瘤患者的不良预后与PDCD4表达的丧失显著相关。因此，我们目前的研究首次表明，在胶质瘤中，PDCD45‘CpG岛甲基化在mRNA水平上阻止了PDCD4的表达。这些结果也表明，PDCD4的重新激活可能是治疗胶质瘤的一种有效的新策略。
Programmed cell death 4 (PDCD4) is a newly described tumour suppressor that inhibits oncogenesis by suppressing gene transcription and translation. Loss of PDCD4 expression has been found in several types of human cancers including the most common cancer of the brain, the gliomas. However, the molecular mechanisms responsible for PDCD4 gene silencing in tumour cells remain unclear. Here we report the identification of 5′CpG island methylation as the predominant cause of PDCD4 mRNA silencing in gliomas. The methylation of the PDCD4 5′CpG island was found in 47% (14/30) of glioma tissues, which was significantly associated with the loss of PDCD4 mRNA expression (γ=−1.000, P < 0.0001). Blocking methylation in glioma cells using a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, restored the PDCD4 gene expression, inhibited their proliferation and reduced their colony formation capacity. Longitudinal studies of a cohort of 84 patients with gliomas revealed that poor prognosis of patients with high-grade tumours were significantly associated with loss of PDCD4 expression. Thus, our current study suggests, for the first time, that PDCD4 5′CpG island methylation blocks PDCD4 expression at mRNA levels in gliomas. These results also indicate that PDCD4 reactivation might be an effective new strategy for the treatment of gliomas.
登录
查看更多内容
影响因子：
8
作者：
Afonja, O;Juste, D;Samuels, HH
通讯作者：
Samuels, HH
DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
DOI：
10.1016/s0006-291x(02)02129-0
发表时间：
2002-09-13
影响因子：
3.1
作者：
Göke, A;Göke, R;Chen, YHH
通讯作者：
Chen, YHH
影响因子：
8
作者：
Bitomsky, N;Böhm, M;Klempnauer, KH
通讯作者：
Klempnauer, KH
DOI：
10.1073/pnas.96.24.14037
发表时间：
1999-11-23
影响因子：
11.1
作者：
Cmarik, JL;Min, HZ;Colburn, NH
通讯作者：
Colburn, NH