Abstract
BackgroundOxidative 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.MethodsWe assessed immunohistochemically the expression of 8-OHdG and Keap1 in precisely characterized material of 69 pancreatic adenocarcinoma patients.ResultsNuclear 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).ConclusionsOxidative 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.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4220521801406476
Highlights
Oxidative stress and redox-regulating enzymes may potentially accelerate pancreatic carcinogenesis and affect chemoresistance
In malignant cells Kelch-like ECH-associated protein 1 (Keap1) immunostaining was found in cytoplasm and on cell membranes
Keap1 expression was recorded in most cases in benign exocrine pancreas and in the islets of Langerhans
Summary
Oxidative stress and redox-regulating enzymes may potentially accelerate pancreatic carcinogenesis and affect chemoresistance. Major antioxidant response regulator NF-E2-related factor 2 (Nrf2) has been linked to poor prognosis in pancreatic cancer. Nrf activity is strictly regulated by oxidative stress sensor Kelch-like ECH-associated protein 1 (Keap). The aim of this study was to evaluate the expression and possible prognostic role of Keap and 8-OHdG in pancreatic cancer. Reactive oxygen species (ROS) are produced mostly as a consequence of aerobic metabolism in mitochondrial respiratory chain. In addition to their crucial role in signal transduction, ROS production is a cornerstone of radiotherapy and may participate to gemcitabine resistance via hypoxia-inducible factor 1α- and nuclear factor κB- mediated CXCR4 up-regulation [4]. Compared to most other solid tumors, these data from in vivo studies are rather limited in pancreatic cancer
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