Keap1 expression has independent prognostic value in pancreatic adenocarcinomas
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RESEARCH
Open Access
Keap1 expression has independent prognostic value in pancreatic adenocarcinomas Joel Isohookana1,2,3, Kirsi-Maria Haapasaari1, Ylermi Soini2 and Peeter Karihtala3*
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. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/ vs/4220521801406476 Keywords: 8-hydroxydeoxyguanosine, Antioxidant enzymes, Keap1, Nrf2, Oxidative stress, Pancreatic cancer
Background Although pancreatic adenocarcinoma is not the one of the most common cancers, it has dismal prognosis, the five year survival being about 5% [1]. At the moment of diagnosis, malignant tissue extends beyond the pancreas in 90% of the cases and metastasis can often be detected [2]. Because of local expansion and early appearance of metastases, tumor is local enough for curative surgical resection only in 10-20% of the cases. Adjuvant chemotherapy with * Correspondence: [email protected] 3 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 Full list of author information is available at the end of the article
gemcitabine is considered in these cases, with slight improvement in survival [3]. Reactive oxygen species (ROS) are pr
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