title: Geographic analysis of RKIP expression and its clinical relevance in colorectal cancer.
abstract: BACKGROUND
  This study evaluates the geographic expression pattern of Raf-1 Kinase Inhibitor Protein (RKIP) in colorectal cancer (CRC) in correlation with clinicopathological and molecular features, markers of epithelial-mesenchymal transition (EMT) and survival outcome.
  
  
  METHODS
  Whole-tissue sections of 220 well-characterised CRCs were immunostained for RKIP. NF-κB and E-Cadherin expression was assessed using a matched multi-punch tissue microarray. Analysis of mismatch repair (MMR) protein expression, B-Raf and KRAS mutations was performed. RKIP expression in normal mucosa, tumour centre, invasion front and tumour buds was each assessed for clinical relevance.
  
  
  RESULTS
  RKIP was diffusely expressed in normal mucosa and progressively lost towards tumour centre and front (P<0.0001). Only 0.9% of tumour buds were RKIP-positive. In the tumour centre, RKIP deficiency predicted metastatic disease (P=0.0307), vascular invasion (P=0.0506), tumour budding (P=0.0112) and an invasive border configuration (P=0.0084). Loss of RKIP correlated with NF-κB activation (P=0.0002) and loss of E-Cadherin (P<0.0001). Absence of RKIP was more common in MMR-deficient cancers (P=0.0191), while no impact of KRAS and B-Raf mutation was observed. RKIP in the tumour centre was identified as a strong prognostic indicator (HR (95% CI): 2.13 (1.27-3.56); P=0.0042) independently of TNM classification and therapy (P=0.0474).
  
  
  CONCLUSIONS
  The clinical relevance of RKIP expression as an independent prognostic factor is restricted to the tumour centre. Loss of RKIP predicts features of EMT and correlates with frequent distant metastasis.
authors: Clinical Pathology Division and Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3010 Bern, Switzerland. viktor.koelzer@pathology.unibe.ch
authors: V H
authors: VH
authors: Koelzer
authors: E
authors: E
authors: Karamitopoulou
authors: H
authors: H
authors: Dawson
authors: A
authors: A
authors: Kondi-Pafiti
authors: I
authors: I
authors: Zlobec
authors: A
authors: A
authors: Lugli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D049488:Phosphatidylethanolamine Binding Protein / Q000032:analysis / Q000378:metabolism*; D011379:Prognosis; D016019:Survival Analysis; D046888:Tissue Array Analysis; D014018:Tissue Distribution
chemical_list: D014408:Biomarkers, Tumor; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein
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