Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells

Hepatology. 2005 Dec;42(6):1329-38. doi: 10.1002/hep.20966.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Bile Duct Neoplasms / metabolism*
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Intrahepatic*
  • Binding Sites
  • Cell Line, Tumor
  • Cholangiocarcinoma / metabolism*
  • Cholangiocarcinoma / pathology
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interleukin-6 / physiology*
  • Janus Kinase 1
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / genetics*
  • Promoter Regions, Genetic
  • Protein-Tyrosine Kinases / physiology
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • STAT3 Transcription Factor / physiology*
  • Up-Regulation


  • Interleukin-6
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • STAT3 Transcription Factor
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • Janus Kinase 1