Institute of Pathological Anatomy, Catholic University of Sacred Heart, Rome, Italy.
Prostate. 2011 Feb 15;71(3):318-25. doi: 10.1002/pros.21245. Epub 2010 Aug 17.
Chronic inflammation and subsequent tissutal alterations may play a key role in prostate carcinogenesis. In this way, molecular alterations of the suppressor of cytokine signaling 3 (SOCS3), one of the most important inhibitory molecule of inflammatory signal transduction circuitries, could contribute to explain the pleiotropic role of interleukin-6 (IL-6) in this type of cancer.
We analyzed the methylation status and mRNA expression of SOCS3 in 20 benign prostate hyperplasias (BPH) and in 51 prostate cancer specimens. We analyzed the SOCS3 methylation status using methylation-specific PCR. Hypermethylation was confirmed by sequencing after subcloning. Epigenetic silencing of this gene was also demonstrated by real-time PCR and by immunohistochemistry. Results and correlation with clinical data were statistically analyzed.
We found that the promoter of SOCS3 was methylated in 39.2% of prostate cancer. On the contrary, all BPH and normal controls had an unmethylated pattern. Real-time analysis showed that in methylated cases SOCS3 mRNA expression was reduced by three and four folds as compared to BPH and unmethylated cases, respectively. Interestingly, SOCS3 mRNA level was higher in unmethylated prostate cancer than in BPH. The immunohistochemical staining analysis for SOCS 3 confirmed mRNA results. Moreover, methylation of SOCS3 promoter significantly associated with intermediate-high grade Gleason score (P = 0.0007) and with an unfavorable clinical outcome (P = 0.0019).
Our data suggest that SOCS3 hypermethylation may be involved in the pathogenesis of prostate cancer and could identify a tumor subset with an aggressive behavior.
慢性炎症及随后的组织改变可能在前列腺癌的发生中起关键作用。在这种情况下，细胞因子信号转导抑制因子 3（SOCS3）的分子改变，作为炎症信号转导通路的最重要抑制分子之一，可能有助于解释白细胞介素 6（IL-6）在这种癌症中的多效作用。
我们分析了 20 例良性前列腺增生（BPH）和 51 例前列腺癌标本中 SOCS3 的甲基化状态和 mRNA 表达。我们使用甲基化特异性 PCR 分析 SOCS3 的甲基化状态。亚克隆后测序证实了超甲基化。通过实时 PCR 和免疫组织化学也证明了该基因的表观遗传沉默。对结果与临床资料进行了统计学分析。
我们发现 SOCS3 的启动子在 39.2%的前列腺癌中发生甲基化。相反，所有 BPH 和正常对照均呈未甲基化模式。实时分析显示，在甲基化病例中，SOCS3 mRNA 表达分别比 BPH 和未甲基化病例减少了 3 倍和 4 倍。有趣的是，未甲基化的前列腺癌中 SOCS3 mRNA 水平高于 BPH。SOCS3 的免疫组织化学染色分析证实了 mRNA 结果。此外，SOCS3 启动子的甲基化与中高级别 Gleason 评分显著相关（P=0.0007），与不良临床结局显著相关（P=0.0019）。
我们的数据表明，SOCS3 高甲基化可能参与了前列腺癌的发病机制，并可能识别出具有侵袭性行为的肿瘤亚群。
