Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing
Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing
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DOI：
10.1053/j.gastro.2006.10.037
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发表时间：
2007-01-01
期刊：
影响因子：
29.4
通讯作者：
Gores, Gregory J.
中科院分区：
文献类型：
--
作者：
Isomoto, Hajime;Mott, Justin L.;Gores, Gregory J.
背景与目的：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）磷酸化。（激活）在胆管癌细胞中异常持续，导致髓样细胞白血病1（Mcl-1）表达增强和对凋亡的抗性。由于细胞因子信号转导抑制因子3（SOCS）通过经典的反馈回路控制IL-6/STAT-3信号通路，因此本研究的目的是检测SOCS-3在人胆管癌中的调节。方法：检测SOCS-3在人胆管癌组织及人胆管癌组织中的表达。细胞系结果：胆管癌组织中磷酸化STAT-3和SOCS-3蛋白表达呈负相关。在那些未能表达SOCS-3的癌症中，SOCS-3启动子的广泛甲基化在肿瘤中被证明，但在配对的非肿瘤组织中没有。同样，在2个胆管癌细胞系中也发现了socs-3启动子甲基化。用去甲基化剂5-氮杂-2 '-脱氧胞苷（DAC）处理恢复了IL-6对SOCS-3的诱导，终止了磷酸-STAT-3应答，并降低了Mcl-1的细胞水平。SOCS-3的增强表达也减少了IL-6对磷酸-STAT-3和Mcl-1的诱导。DAC处理或强制SOCS-3表达使细胞对TRAIL介导的凋亡敏感。结论：胆管癌中SOCS-3表观遗传沉默与持续的IL-6/STAT-3信号转导和Mcl-1表达增强有关。
Background & Aims: Interleukin 6 (IL-6)-mediated signal transducers and activators of transcription 3 (STAT-3) phosphorylation. (activation) is aberrandy sustained in cholangiocardnoma cells resulting in enhanced myeloid cell leukemia 1 (Mcl-1) expression and resistance to apoptosis. Because suppressor of cytokine signaling 3 (SOCS) controls the IL-6/STAT-3 signaling pathway by a classic feedback loop, the aims of this study were to examine SOCS-3 regulation in human cholangiocarcinoma. Methods: SOCS-3 expression was assessed in human cholangiocardnoma tissue and the Mz-ChA-1 and CCLP1 human cholangiocarcinoma. cell lines. Results: An inverse correlation was observed between phospho-STAT-3 and SOCS-3 protein expression in cholangiocarcinonia. In those cancers failing to express SOCS-3, extensive methylation of the SOCS-3 promoter was demonstrated in tumor but not in paired nontumor tissue. Likewise, methylation of the socs-3 promoter was also identified in 2 cholangiocarcinoma cell lines. Treatment with a demethylating agent, 5-aza-2'-deoxycytidine (DAC), restored IL-6 induction of SOCS-3, terminated the phospho-STAT-3 response, and reduced cellular levels of Mcl-1. Enforced expression of SOCS-3 also reduced IL-6 induction of phospho-STAT-3 and Mcl-1. Either DAC treatment or enforced SOCS-3 expression sensitized the cells to TRAIL-mediated apoptosis. Conclusions: SOCS-3 epigenetic silencing is responsible for sustained IL-6/STAT-3 signaling and enhanced Mcl-1 expression in cholangiocarcinoma.