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.
Apoptosis, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Cell Line, Tumor, Cholangiocarcinoma, CpG Islands, DNA Methylation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Interleukin-6, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins, Phosphorylation, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-2, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, TNF-Related Apoptosis-Inducing Ligand, Tyrosine
Isomoto, Hajime; Mott, Justin L.; Kobayashi, Shogo; Werneburg, Nathan W.; Bronk, Steve F.; Haan, Serge; and Gores, Gregory J., "Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing." (2007). Journal Articles: Biochemistry & Molecular Biology. 2.