Martini Maurizio, Pallini Roberto, Luongo Giuseppe, Cenci Tonia, Lucantoni Corrado, Larocca Luigi Maria
Department of Pathology, Catholic University of Sacred Heart, Rome, Italy.
Int J Cancer. 2008 Dec 15;123(12):2955-60. doi: 10.1002/ijc.23805.
Alterations in the signal transduction pathways are key mechanisms in the pathogenesis of de novo glioblastoma multiforme (GBM), which are also involved in the resistance to chemo- and radiotherapy. Here, we analyzed the methylation status and mRNA expression of suppressor of cytokine signaling (SOCS)1-2-3, 3 of the most important inhibitory molecules of the signal transduction circuitry, in 46 GBM specimens. The relationship between methylation status of SOCS1-2-3 and clinical outcome was investigated. Using methylation-specific PCR (MS-PCR) and sequencing, after bisulphite modification, we found that the promoter of SOCS1-2-3 was methylated in 24, 6.5 and 35% of GBM, respectively. Real-time analysis showed that in methylated GBM, mRNA expression for SOCS1-2-3 was reduced by 5, 3 and 7-folds, respectively, when compared with unmethylated GBM. Moreover, methylation of SOCS3 promoter significantly associated with an unfavorable clinical outcome (p < 0.0002). Our data suggest that methylation of SOCS3 may be involved in the pathogenesis of GBM and in the resistance of this neoplasm to conventional treatment.
信号转导通路的改变是原发性多形性胶质母细胞瘤（GBM）发病机制中的关键机制，其也参与了对化疗和放疗的耐药性。在此，我们分析了46例GBM标本中细胞因子信号转导抑制因子（SOCS）1-2-3（信号转导通路中3个最重要的抑制分子）的甲基化状态和mRNA表达。研究了SOCS1-2-3甲基化状态与临床结局之间的关系。使用甲基化特异性PCR（MS-PCR）和测序，经亚硫酸氢盐修饰后，我们发现GBM中SOCS1-2-3的启动子甲基化率分别为24%、6.5%和35%。实时分析表明，与未甲基化的GBM相比，甲基化的GBM中SOCS1-2-3的mRNA表达分别降低了5倍、3倍和7倍。此外，SOCS3启动子的甲基化与不良临床结局显著相关（p<0.0002）。我们的数据表明，SOCS3的甲基化可能参与了GBM的发病机制以及该肿瘤对传统治疗的耐药性。
