title: MiR-23a/-24-induced gene silencing results in mesothelial cell integration of pancreatic cancer.
abstract: BACKGROUND
  Invasion of the surrounding tissue is part of the metastatic cascade. Here, we examined the invasion of pancreatic ductal adenocarcinoma (PDAC) cells into the mesothelial barrier and identified the related microRNA (miRNA) expression profiles.
  
  
  METHODS
  The interactions between PDAC cells and mesothelial monolayers were characterised and quantified using a specific time-lapse videomicroscopy assay. Pancreatic ductal adenocarcinoma cells were further evaluated using the adhesion assay, and miRNA, mRNA and protein expressions were determined using microarray, q-RT-PCR and western blots, respectively. These data were correlated with in vivo dissemination scores.
  
  
  RESULTS
  Two groups of PDAC cell lines were distinguished by their integration capacity into the mesothelial monolayer using mean elongation factors (MEFs). Adhesion assays showed a concordant relation between adhesive properties and integration capacity. The distant metastases scores were reverse correlated with MEFs. Microarray analysis of these groups revealed that miR-23a and/or miR-24 target for FZD5, HNF1B and/or TMEM92, respectively, and that they are significantly deregulated.
  
  
  CONCLUSIONS
  MiR-23a and/or miR-24 overexpression leads to gene silencing of FZD5, TMEM92 and/or HNF1B. Their downregulation induces deregulated expression and degradation of E-cadherin and β-catenin causing destabilisation of the cadherin/catenin complex, and altered the expression of Wnt-related genes. We propose a molecular (epi)genetic mechanism by which increased EMT-like cell shape transformation and integration into mesothelial monolayers of PDAC cells can be observed.
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Muenster, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Listing
authors.affiliation: Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany.
authors.forename: W A
authors.initials: WA
authors.lastname: Mardin
authors.affiliation: Arrows Biomedical Deutschland GmbH, Muenster, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wohlfromm
authors.affiliation: Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany.
authors.forename: S T
authors.initials: ST
authors.lastname: Mees
authors.affiliation: Comprehensive Cancer Center Muenster, University Hospital Muenster, Albert-Schweitzer-Campus 1, Muenster 48149, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Haier
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000235:genetics*; D045744:Cell Line, Tumor; D004848:Epithelium / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D046888:Tissue Array Analysis
chemical_list: C552430:MIRN23a microRNA, human; C543845:MIRN24 microRNA, human; D035683:MicroRNAs