Isohookana Joel, Haapasaari Kirsi-Maria, Soini Ylermi, Karihtala Peeter
Department of Pathology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 50, 90020, Oulu University Hospital, Finland.
Department of Pathology and Forensic Medicine, University of Eastern Finland, Cancer Center of Eastern Finland, PO Box 1627, 70211, Kuopio, Finland.
Diagn Pathol. 2015 Apr 16;10:28. doi: 10.1186/s13000-015-0258-4.
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.
We assessed immunohistochemically the expression of 8-OHdG and Keap1 in precisely characterized material of 69 pancreatic adenocarcinoma patients.
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).
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.
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氧化应激和氧化还原调节酶可能会加速胰腺癌的发生，还会影响化疗耐药性。最近，主要的抗氧化反应调节因子核因子E2相关因子2（Nrf2）与胰腺癌的不良预后有关。Nrf2的活性受氧化应激传感器kelch样ECH相关蛋白1（Keap1）严格调控。氧化DNA损伤可通过8-羟基-2'-脱氧鸟苷（8-OHdG）的表达来评估。本研究的目的是评估Keap1和8-OHdG在胰腺癌中的表达及可能的预后作用。
我们采用免疫组织化学方法评估了69例胰腺腺癌患者经精确特征化处理的样本中8-OHdG和Keap1的表达。
细胞核8-OHdG与细胞质Keap1的表达相关（p = 0.031），在肿瘤较小的患者中过度表达（p = 0.016），且在无淋巴结转移的肿瘤中也过度表达（p = 0.051）。细胞质8-OHdG的表达与较高的分化程度相关（p = 0.023）。细胞质Keap1免疫染色与N0分期相关（p = 0.0009），且与无远处转移相关（p = 0.018）。膜性Keap1与更长的无复发生存期相关（p = 0.041）以及与胰腺癌特异性生存期相关（中位生存期分别为14个月和32个月；p = 0.029），并且在多因素分析中是胰腺癌相关死亡的独立预后因素（风险比2.66，95%置信区间1.23 - 5.75）。
氧化应激和主要的氧化还原调节因子可能参与胰腺癌的发生，并且Keap1似乎是胰腺癌中一个有前景的预后因素。未来的研究还应关注氧化还原调节与胰腺癌化疗耐药性之间的潜在联系。
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