title: Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells.
abstract: OBJECTIVE
  In both pancreatic cancer and chronic pancreatitis, there is enhanced expression of mitogenic growth factors and their tyrosine kinase receptors, which have the capacity to activate mitogen-activated protein kinase (MAPK). In view of the important role of MAPK kinase phosphatase (MKP)-1 in the regulation of MAPK activation, the expression and functional role of MKP-1 was analyzed.
  
  
  METHODS
  Pancreatic tissues were analyzed by Northern blotting, Western blotting, and immunohistochemistry. Pancreatic cancer cells were transfected with a full-length MKP-1 antisense construct. Growth characteristics and tumorigenicity in vivo and the effects of mitogenic growth factors on cell growth and MAPK activation were determined in transfected and control cells.
  
  
  RESULTS
  MKP-1 messenger RNA (mRNA) levels were increased in pancreatic cancer and chronic pancreatitis (CP) tissues. Moderate to strong MKP-1 immunoreactivity was present in the cancer cells, ductal cells of pancreatic intraepithelial neoplasia, and in tubular complexes in CP. Down-regulation of MKP-1 resulted in decreased anchorage-dependent and -independent growth of pancreatic cancer cells, and decreased tumorigenicity in a nude mouse tumor model. MKP-1 down-regulation led to decreased proliferation and sustained MAPK activation in response to mitogens.
  
  
  CONCLUSIONS
  Suppression of MKP-1 expression reduces the tumorigenicity of pancreatic cancer cells in vivo, suggesting that MKP-1 contributes to enhanced mitogenic signaling in pancreatic cancer cells.
authors.affiliation: Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
authors.forename: Quan
authors.initials: Q
authors.lastname: Liao
authors.forename: Junchao
authors.initials: J
authors.lastname: Guo
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.forename: Arthur
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins; D002908:Chronic Disease; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D010179:Pancreas / Q000201:enzymology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000517:prevention & control; D010195:Pancreatitis / Q000201:enzymology; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases