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.