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Interleukin 6 upregulates myeloid cell leukemia‐1 expression through a STAT3 pathway in cholangiocarcinoma cells
Author(s) -
Isomoto Hajime,
Kobayashi Shogo,
Werneburg Nathan W.,
Bronk Steve F.,
Guicciardi Maria Eugenia,
Frank David A.,
Gores Gregory J.
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20966
Subject(s) - stat3 , cancer research , janus kinase , stat protein , myeloid leukemia , transcription factor , chromatin immunoprecipitation , janus kinase 2 , biology , downregulation and upregulation , microbiology and biotechnology , promoter , signal transduction , gene expression , gene , biochemistry
Abstract Interleukin 6 (IL‐6) contributes to the pathogenesis of cholangiocarcinoma by upregulating myeloid cell leukemia‐1 (Mcl‐1), a key antiapoptotic Bcl‐2 family member protein. IL‐6 can alter gene transcription via Janus kinases (JAK) and signal transducer and activator of transcription (STAT) signal cascade. We examined this cascade in IL‐6 regulation of Mcl‐1 transcription in human cholangiocarcinoma cell lines. STAT3 was constitutively activated ( i . e ., tyrosine‐phosphorylated) in cholangiocarcinoma cells but not in nonmalignant cholangiocytes. Treatment with anti–IL‐6 antisera or the JAK inhibitor AG490 or transfection with dominant negative STAT3 diminished Mcl‐1 messenger RNA and protein levels. Likewise, these attempts to interrupt the STAT3 cascade also reduced Mcl‐1 promoter activity. Site‐directed mutagenesis of a putative STAT3 consensus binding sequence decreased Mcl‐1 promoter activity. Chromatin immunoprecipitation analysis demonstrated a direct binding of STAT3 to the putative STAT3 binding sequences in the Mcl‐1 promoter. Downregulation of Mcl‐1 by AG490 sensitized the cells to apoptosis mediated by tumor necrosis factor–related apoptosis‐inducing ligand. In conclusion , we have directly demonstrated a STAT3 regulatory element in the Mcl‐1 promoter. Downregulation of Mcl‐1 transcription by inhibiting this cascade is a potential strategy for the treatment of this cancer.(H EPATOLOGY 2005;42:1329–1338.)