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Apoptosis/physiology; Bile Duct Neoplasms/genetics/metabolism/pathology; Bile Ducts, Intrahepatic/metabolism/pathology; Cell Line, Tumor; Cholangiocarcinoma/genetics/metabolism/pathology; CpG Islands/physiology; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Interleukin-6/metabolism; Neoplasm Proteins/metabolism; Phosphorylation; Promoter Regions, Genetic/physiology; Proto-Oncogene Proteins c-bcl-2/metabolism; STAT3 Transcription Factor/metabolism; Suppressor of Cytokine Signaling Proteins/genetics/metabolism; TNF-Related Apoptosis-Inducing Ligand/metabolism; Tyrosine/metabolism
[en] BACKGROUND & AIMS: Interleukin 6 (IL-6)-mediated signal transducers and activators of transcription 3 (STAT-3) phosphorylation (activation) is aberrantly sustained in cholangiocarcinoma 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 cholangiocarcinoma 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 cholangiocarcinoma. 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.