title: Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis.
abstract: OBJECTIVE
  Human pancreatic adenocarcinoma has an overall poor prognosis. Therapeutic efforts are often ineffective because of late diagnosis and a high degree of chemoresistance. Overexpression of transforming growth factor alpha in the pancreas of transgenic mice causes the formation of premalignant ductal lesions and the development of invasive ductal adenocarcinoma. The aim of the present study was to explore regulation of proapoptotic and antiapoptotic signals during pancreatic tumor development in mice.
  
  
  METHODS
  EL-TGFalpha-hGH transgenic mice crossbred to p53-deficient mice develop ductal pancreatic adenocarcinoma resembling the human disease. During the multistep carcinogenesis up-regulation of Bcl-x(L) is evident early and persists throughout tumorigenesis as detected by Real Time PCR, Western blot analysis, and immunofluorescence.
  
  
  RESULTS
  Up-regulation of Bcl-x(L) is evident early in tumor development and persists throughout tumorigenesis. The transcription factors Stat3 and NF-kappaB induce increased Bcl-x(L) expression in the premalignant lesions and tumor cells. Inhibition of either transcription factor alone leads to Bcl-x(L) down-regulation in transient transfection assays. Functional analysis shows that blocking of both Stat3 and NF-kappaB together induces programmed cell death in murine pancreatic tumor cells.
  
  
  CONCLUSIONS
  These findings indicate that apoptosis resistance precedes formation of invasive pancreatic cancer. Therefore, combined inhibition of Stat3 and NF-kappaB might represent a novel strategy for tumor prevention and therapy.
authors.affiliation: Internal Medicine II, Technical University of Munich, Germany.
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
authors.forename: Christoph K
authors.initials: CK
authors.lastname: Weber
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.forename: Guido
authors.initials: G
authors.lastname: Adler
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010641:Phenotype; D011230:Precancerous Conditions / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein