Keap1 expression has independent prognostic value in pancreatic adenocarcinomas. 2015

Joel Isohookana, and Kirsi-Maria Haapasaari, and Ylermi Soini, and Peeter Karihtala
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.

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.

UI MeSH Term Description Entries
D007150 Immunohistochemistry Histochemical localization of immunoreactive substances using labeled antibodies as reagents. Immunocytochemistry,Immunogold Techniques,Immunogold-Silver Techniques,Immunohistocytochemistry,Immunolabeling Techniques,Immunogold Technics,Immunogold-Silver Technics,Immunolabeling Technics,Immunogold Silver Technics,Immunogold Silver Techniques,Immunogold Technic,Immunogold Technique,Immunogold-Silver Technic,Immunogold-Silver Technique,Immunolabeling Technic,Immunolabeling Technique,Technic, Immunogold,Technic, Immunogold-Silver,Technic, Immunolabeling,Technics, Immunogold,Technics, Immunogold-Silver,Technics, Immunolabeling,Technique, Immunogold,Technique, Immunogold-Silver,Technique, Immunolabeling,Techniques, Immunogold,Techniques, Immunogold-Silver,Techniques, Immunolabeling
D008207 Lymphatic Metastasis Transfer of a neoplasm from its primary site to lymph nodes or to distant parts of the body by way of the lymphatic system. Lymph Node Metastasis,Lymph Node Metastases,Lymphatic Metastases,Metastasis, Lymph Node
D010084 Oxidation-Reduction A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). Redox,Oxidation Reduction
D010190 Pancreatic Neoplasms Tumors or cancer of the PANCREAS. Depending on the types of ISLET CELLS present in the tumors, various hormones can be secreted: GLUCAGON from PANCREATIC ALPHA CELLS; INSULIN from PANCREATIC BETA CELLS; and SOMATOSTATIN from the SOMATOSTATIN-SECRETING CELLS. Most are malignant except the insulin-producing tumors (INSULINOMA). Cancer of Pancreas,Pancreatic Cancer,Cancer of the Pancreas,Neoplasms, Pancreatic,Pancreas Cancer,Pancreas Neoplasms,Pancreatic Acinar Carcinoma,Pancreatic Carcinoma,Acinar Carcinoma, Pancreatic,Acinar Carcinomas, Pancreatic,Cancer, Pancreas,Cancer, Pancreatic,Cancers, Pancreas,Cancers, Pancreatic,Carcinoma, Pancreatic,Carcinoma, Pancreatic Acinar,Carcinomas, Pancreatic,Carcinomas, Pancreatic Acinar,Neoplasm, Pancreas,Neoplasm, Pancreatic,Neoplasms, Pancreas,Pancreas Cancers,Pancreas Neoplasm,Pancreatic Acinar Carcinomas,Pancreatic Cancers,Pancreatic Carcinomas,Pancreatic Neoplasm
D002423 Cause of Death Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. Causes of Death,Death Cause,Death Causes
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D003849 Deoxyguanosine A nucleoside consisting of the base guanine and the sugar deoxyribose.
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072019 Kelch-Like ECH-Associated Protein 1 An adaptor protein characterized by an N-terminal BTB-POZ DOMAIN and six KELCH REPEATS that functions as a substrate for the E3 UBIQUITIN LIGASE complex. It negatively-regulates NF-E2-RELATED FACTOR 2 by targeting it for ubiquitination and degradation by the PROTEASOME. It also represses genes regulated by ANTIOXIDANT RESPONSE ELEMENTS. KEAP-1 Protein,KEAP1 Protein,KEAP 1 Protein,Kelch Like ECH Associated Protein 1
D000080242 8-Hydroxy-2'-Deoxyguanosine Common oxidized form of deoxyguanosine in which C-8 position of guanine base has a carbonyl group. 2'-Deoxy-7,8-Dihydro-8-Oxoguanosine,2'-Deoxy-8-Hydroxyguanosine,2'-Deoxy-8-Oxo-7,8-Dihydroguanosine,2'-Deoxy-8-Oxoguanosine,7,8-Dihydro-8-Oxo-2'-Deoxyguanosine,7-Hydro-8-Oxodeoxyguanosine,8-Hydroxydeoxyguanosine,8-Oxo-2'-Deoxyguanosine,8-Oxo-7,8-Dihydro-2'-Deoxyguanosine,8-Oxo-7,8-Dihydrodeoxyguanosine,8-Oxo-7-Hydrodeoxyguanosine,8-Oxo-Deoxyguanosine,8OHdG,8-OH-dG,8-oxo-dG,8-oxo-dGuo,8-oxodG,8-oxodGuo,2' Deoxy 7,8 Dihydro 8 Oxoguanosine,2' Deoxy 8 Hydroxyguanosine,2' Deoxy 8 Oxo 7,8 Dihydroguanosine,2' Deoxy 8 Oxoguanosine,7 Hydro 8 Oxodeoxyguanosine,7,8 Dihydro 8 Oxo 2' Deoxyguanosine,8 Hydroxy 2' Deoxyguanosine,8 Hydroxydeoxyguanosine,8 Oxo 2' Deoxyguanosine,8 Oxo 7 Hydrodeoxyguanosine,8 Oxo 7,8 Dihydro 2' Deoxyguanosine,8 Oxo 7,8 Dihydrodeoxyguanosine,8 Oxo Deoxyguanosine

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