Epigenetic Alterations in Cholangiocarcinoma-Sustained IL-6/STAT3 Signaling in Cholangiocarcinoma due to SOCS3 Epigenetic Silencing
Epigenetic Alterations in Cholangiocarcinoma-Sustained IL-6/STAT3 Signaling in Cholangiocarcinoma due to SOCS3 Epigenetic Silencing
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DOI：
10.1159/000167859
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发表时间：
2009-01-01
期刊：
影响因子：
3.2
通讯作者：
Isomoto, Hajime
中科院分区：
文献类型：
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作者：
Isomoto, Hajime
胆管癌（Cholangiocarcinoma，CCA）是一种起源于胆管上皮的高致死性恶性肿瘤，临床表现较晚，缺乏有效的治疗手段。慢性炎症性疾病，包括原发性硬化性胆管炎，肝吸虫感染和肝内胆管结石，被列为危险因素，但对于大多数CCA病例，原因尚不清楚。分子发病机制的最新进展强调了表观遗传学改变的重要性，除了胆管癌发生过程中的遗传变化之外，还包括启动子高甲基化和组蛋白脱乙酰化。本文就CCA中高甲基化基因及其在胆管癌发生中的作用作一综述。在高甲基化基因中，我们发现CCA中细胞因子信号转导抑制因子3（SOCS 3）基因启动子CpG岛的高甲基化。白细胞介素-6（IL-6）介导的信号转导和转录激活因子3（STAT 3）激活在CCA细胞中异常持续，导致对凋亡的抵抗。SOCS 3通过经典的反馈回路控制IL-6/STAT 3信号通路。事实上，SOCS 3表观遗传沉默负责CCA中持续的IL-6/STAT 3信号传导。这些发现为表观遗传疗法恢复这种癌症中的SOCS 3提供了新的前景。版权所有（c）2009 S. Karger AG，巴塞尔
Cholangiocarcinoma (CCA) is a highly lethal malignant tumor arising from the biliary tract epithelium, characterized by its typically late clinical presentation and lack of effective therapeutic modalities. Chronic inflammatory conditions, including primary sclerosing cholangitis, liver fluke infestation and hepatolithiasis, are listed in the risk factors, but for most cases of CCA the cause is unknown. Recent advances in molecular pathogenesis have highlighted the importance of epigenetic alterations including promoter hypermethylation and histone deacetylation in addition to genetic changes in the process of cholangiocarcinogenesis. This review provides a comprehensive overview of the genes hypermethylated in CCA to date and their putative roles in cholangiocarcinogenesis. Among genes hypermethylated, we found the CpG island hypermethylation in suppressor of cytokine signaling 3 (SOCS3) gene promoter in CCA. Interleukin-6 (IL-6)-mediated signal transducers and activators of transcription 3 (STAT3) activation are aberrantly sustained in CCA cells, resulting in resistance to apoptosis. SOCS3 controls the IL-6/STAT3 signaling pathway by a classic feedback loop. Indeed, SOCS3 epigenetic silencing is responsible for sustained IL-6/STAT3 signaling in CCA. These findings provide new perspectives for epigenetic therapy to restore SOCS3 in this cancer. Copyright (c) 2009 S. Karger AG, Basel