title: Loss of Raf-1 kinase inhibitor protein (RKIP) is strongly associated with high-grade tumor budding and correlates with an aggressive phenotype in pancreatic ductal adenocarcinoma (PDAC).
abstract: BACKGROUND
  Raf-1 kinase inhibitor protein (RKIP) has emerged as a significant metastatic suppressor in a variety of human cancers and is known to inhibit Ras/Raf/MEK/ERK signaling. By suppressing the activation of the NFkB/SNAIL circuit, RKIP can regulate the induction of epithelial-mesenchymal transition (EMT). The aim of this study was to evaluate RKIP expression and to determine its association with clinicopathological features, including EMT in form of tumor budding in pancreatic ductal adenocarcinoma (PDAC).
  
  
  METHODS
  Staining for RKIP was performed on a multipunch Tissue Microarray (TMA) of 114 well-characterized PDACs with clinico-pathological, follow-up and adjuvant therapy information. RKIP-expression was assessed separately in the main tumor body and in the tumor buds. Another 3 TMAs containing normal pancreatic tissue, precursor lesions (Pancreatic Intraepithelial Neoplasia, PanINs) and matched lymph node metastases were stained in parallel. Cut-off values were calculated by receiver operating characteristic (ROC) curve analysis.
  
  
  RESULTS
  We found a significant progressive loss of RKIP expression between normal pancreatic ductal epithelia (average: 74%), precursor lesions (PanINs; average: 37%), PDAC (average 20%) and lymph node metastases (average 8%, p<0.0001). RKIP expression was significantly lower in tumor buds (average: 6%) compared to the main tumor body (average 20%; p<0.005). RKIP loss in the tumor body was marginally associated with advanced T-stage (p=0.0599) as well as high-grade peritumoral (p=0.0048) and intratumoral budding (p=0.0373). RKIP loss in the buds showed a clear association with advanced T stage (p=0.0089).
  
  
  CONCLUSIONS
  The progressive loss of RKIP seems to play a major role in the neoplastic transformation of pancreas, correlates with aggressive features in PDAC and is associated with the presence of EMT in form of tumor budding.
authors: Clinical Pathology Division, University of Bern, Murtenstrasse 31, Bern, Switzerland. eva.diamantis@pathology.unibe.ch.
authors: Eva
authors: E
authors: Karamitopoulou
authors: Inti
authors: I
authors: Zlobec
authors: Beat
authors: B
authors: Gloor
authors: Agathi
authors: A
authors: Kondi-Pafiti
authors: Alessandro
authors: A
authors: Lugli
authors: Aurel
authors: A
authors: Perren
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000502:physiology*
chemical_list: C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein