title: Keap1 expression has independent prognostic value in pancreatic adenocarcinomas.
abstract: BACKGROUND
  Oxidative stress and redox-regulating enzymes may potentially accelerate pancreatic carcinogenesis and also affect chemoresistance. Recently major antioxidant response regulator NF-E2-related factor 2 (Nrf2) has been linked to poor prognosis in pancreatic cancer. Nrf2 activity is strictly regulated by oxidative stress sensor Kelch-like ECH-associated protein 1 (Keap1). Oxidative DNA damage can be estimated e.g. by 8-hydroxy-2'-deoxyguanosine (8-OHdG) expression. The aim of this study was to evaluate the expression and possible prognostic role of Keap1 and 8-OHdG in pancreatic cancer.
  
  
  METHODS
  We assessed immunohistochemically the expression of 8-OHdG and Keap1 in precisely characterized material of 69 pancreatic adenocarcinoma patients.
  
  
  RESULTS
  Nuclear 8-OHdG associated with cytoplasmic Keap1 expression (p = 0.031) and was overexpressed in patients with smaller tumors (p = 0.016) and in tumors without lymph node involvement (p = 0.051). Cytoplasmic 8-OHdG expression associated with higher differentiation (p = 0.023). Cytoplasmic Keap1 immunostaining associated with N0-staging (p = 0.0009) and the absence of distant metastases (p = 0.018). Membranous Keap1 associated with longer relapse-free survival (p = 0.041) and pancreatic cancer-specific survival (median survival 14 vs. 32 months; p = 0.029) and was in multivariate analysis an independent prognostic factor of pancreatic cancer-related death (HR 2.66, 95%CI 1.23-5.75).
  
  
  CONCLUSIONS
  Oxidative stress and main redox regulators may participate in pancreatic carcinogenesis and Keap1 appears as a promising prognostic factor in pancreatic cancer. Future studies should also concentrate on potential link between redox regulation and chemoresistance in pancreatic cancer.
  The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4220521801406476.
authors: Department of Pathology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 50, 90020, Oulu University Hospital, Finland. joel.isohookana@student.oulu.fi.|Department of Pathology and Forensic Medicine, University of Eastern Finland, Cancer Center of Eastern Finland, PO Box 1627, 70211, Kuopio, Finland. joel.isohookana@student.oulu.fi.|Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 22, 90029, Oulu University Hospital, Finland. joel.isohookana@student.oulu.fi.
authors: Joel
authors: J
authors: Isohookana
authors: Department of Pathology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 50, 90020, Oulu University Hospital, Finland. kirsi-maria.haapasaari@ppshp.fi.
authors: Kirsi-Maria
authors: KM
authors: Haapasaari
authors: Department of Pathology and Forensic Medicine, University of Eastern Finland, Cancer Center of Eastern Finland, PO Box 1627, 70211, Kuopio, Finland. ylermi.soini@uef.fi.
authors: Ylermi
authors: Y
authors: Soini
authors: Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 22, 90029, Oulu University Hospital, Finland. peeter.karihtala@oulu.fi.
authors: Peeter
authors: P
authors: Karihtala
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000230:Adenocarcinoma / Q000737:chemistry* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D014408:Biomarkers, Tumor / Q000032:analysis*; D002423:Cause of Death; D002454:Cell Differentiation; D016009:Chi-Square Distribution; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis*; D053208:Kaplan-Meier Estimate; D000072019:Kelch-Like ECH-Associated Protein 1; D008207:Lymphatic Metastasis; D015999:Multivariate Analysis; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine