title: Slug-dependent upregulation of L1CAM is responsible for the increased invasion potential of pancreatic cancer cells following long-term 5-FU treatment.
abstract: BACKGROUND
  Pancreatic adenocarcinoma is a lethal disease with 5-year survival of less than 5%. 5-fluorouracil (5-FU) is a principal first-line therapy, but treatment only extends survival modestly and is seldom curative. Drug resistance and disease recurrence is typical and there is a pressing need to overcome this. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc 03.27 cell line by long-term exposure to increasing doses of 5-FU.
  
  
  RESULTS
  5-FU-resistant cell lines exhibited increased expression of markers associated with multidrug resistance explaining their reduced sensitivity to 5-FU. In addition, 5-FU-resistant cell lines showed alterations typical for an epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, and a significant upregulation of L1CAM was seen on the RNA and protein level. In pancreatic cancer, expression of L1CAM is associated with a chemoresistant and migratory phenotype. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with antibodies, we show that the increased invasiveness observed in the chemoresistant cells functionally depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we demonstrate that in the chemoresistant cell lines, L1CAM expression depends on Slug rather than β-catenin.
  
  
  CONCLUSIONS
  Our findings establish Slug-induced L1CAM expression as a mediator of a chemoresistant and migratory phenotype in pancreatic adenocarcinoma cells.
authors: Unit for Cell Signaling, Institute of Microbiology, Cancer Stem Cell, Innovation Center (CAST), Rikshospitalet, Oslo, Norway.
authors: Kaja
authors: K
authors: Lund
authors: Unit for Cell Signaling, Institute of Microbiology, Cancer Stem Cell, Innovation Center (CAST), Rikshospitalet, Oslo, Norway; Norwegian Institute of Public Health, Division of Infectious Disease Control, Department of Bacteriology and Immunology, Oslo, Norway.
authors: Jennifer L
authors: JL
authors: Dembinski
authors: Unit for Cell Signaling, Institute of Microbiology, Cancer Stem Cell, Innovation Center (CAST), Rikshospitalet, Oslo, Norway.
authors: Nina
authors: N
authors: Solberg
authors: Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, Oslo, Norway; Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors: Alfonso
authors: A
authors: Urbanucci
authors: Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, Oslo, Norway; Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department of Urology, Oslo University Hospital, Oslo, Norway, Centre for Molecular Medicine of Urology, Oslo University Hospital, Oslo, Norway.
authors: Ian G
authors: IG
authors: Mills
authors: Unit for Cell Signaling, Institute of Microbiology, Cancer Stem Cell, Innovation Center (CAST), Rikshospitalet, Oslo, Norway.
authors: Stefan
authors: S
authors: Krauss
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
chemical_list: D039842:Neural Cell Adhesion Molecule L1; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; D005472:Fluorouracil