The Clinicopathological and Prognostic Significance of Nrf2 and Keap1 Expression in Hepatocellular Carcinoma

Abstract

Nuclear factor E2-related factor2 (Nrf2) activation is associated with both cytoprotective effects and malignant behavior of cancer cells. This study aimed to evaluate the clinicopathological implications of the expression of Nrf2, pNrf2, and its regulator Keap1 in human hepatocellular carcinomas (HCCs). Tissue microarrays consisting of 285 surgically resected HCCs were immunohistochemically stained with pNrf2, Nrf2, Keap1, stemness-related markers (keratin 19 (K19), epithelial cell adhesion molecule (EpCAM)), carbonic anhydrase IX (CAIX), epithelial-mesenchymal transition (EMT)-related markers (ezrin, uPAR, E-cadherin), and p53, and the results were correlated with the clinicopathological features. pNrf2 expression was significantly associated with increased proliferative activity, as well as EpCAM, ezrin, p53, and CAIX expression and E-cadherin loss (p < 0.05, all). Strong cytoplasmic Nrf2 expression was associated with CAIX and ezrin expression (p < 0.05, both). Keap1 was associated with increased proliferative activity, portal vein invasion, EMT-related markers, and p53 expression in CAIX-negative HCCs (p < 0.05, all). Both pNrf2 and cytoplasmic Nrf2 expression were associated with decreased overall survival (p < 0.05, both), and cytoplasmic Nrf2 expression was an independent predictor of decreased overall survival on multivariate analysis (hazard ratio 4.15, p < 0.001). Both pNrf2 and cytoplasmic Nrf2 expression were associated with poor survival and aggressive behavior of HCC. In addition, Keap1 expression was also associated with aggressive HCC behavior in CAIX-negative HCCs, suggesting that Keap1 expression should be interpreted in the context of hypoxia status.