Reference : Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic ...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing.
Isomoto, Hajime [> >]
Mott, Justin L. [> >]
Kobayashi, Shogo [> >]
Werneburg, Nathan W. [> >]
Bronk, Steve F. [> >]
Haan, Serge mailto [Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > Institute for Biochemistry]
Gores, Gregory J. [> >]
Yes (verified by ORBilu)
United States
[en] 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.

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