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.

Downregulation of CYP39A1 Serves as a Novel Biomarker in Hepatocellular Carcinoma with Worse Clinical Outcome

“…In addition, in order to study the possible mechanism of CYP39A1 in HCC, the related protein with HCC was detected. It was reported that NF-κB and Nrf2 was activated in HCC [33][34][35][36], which was also found in our HCC model group with the downregulation of CYP39A1. However, CYP39A1 expression was increased after treating with osthole, while p-NF-κB and Nrf2 protein expression were decreased.…”

Antioral Squamous Cell Carcinoma Effects of Carvacrol via Inhibiting Inflammation, Proliferation, and Migration Related to Nrf2/Keap1 Pathway

“…Combining clinicopathological information, Nrf2 expression was positively correlated to differentiation and lymph node metastasis of OSCC, indicating that it could be an underlying prognostic factor. Recently, Nrf2 could become an independent predictor for clinical outcomes of hepatocellular carcinoma [ 23 ]. Overexpression of Nrf2 promoted OSCC cell proliferation and migration, and the opposite results were found when there was depletion of Nrf2.…”

SOCS3-mediated activation of p53-p21-NRF2 axis and cellular adaptation to oxidative stress in SOCS1-deficient hepatocellular carcinoma

“…NRF2-deficient mice have clearly established an oncogenic role for NRF2 activation in DENinduced HCC 42 and NRF2-high HCC patients show poor survival 43,44 . Even though mutations that disrupt KEAP-NRF2 interactions contribute to NRF2 activation in human and rodent HCC 45,46 , NRF2 activation in HCC can also occur by other mechanisms such as elevated expression of p62 47 .…”