Abstract
Nrf2, a master regulator of oxidative stress, is considered a prominent target for prevention of hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide. Here we report that Nrf2-deficient mice resisted diethylnitrosamine (DEN)-induced hepatocarcinogenesis without affecting P450-mediated metabolic activation of DEN. Nrf2 expression, nuclear translocation, and transcriptional activity were enhanced in liver tumors. Overactivated Nrf2 was required for hepatoma growth in DEN-induced HCC. Following DEN treatment, Nrf2 genetic disruption reduced expression of pentose phosphate pathway-related enzymes, the depletion of which has been associated with an amelioration of HCC incidence. Conversely, enhanced Nrf2 activity was attributable to alterations in the ability to bind its endogenous inhibitor Keap1. Our findings provide a mechanistic rationale for Nrf2 blockade to prevent and possibly treat liver cancer. Cancer Res; 77(18); 4797-808. ©2017 AACR.
Highlights
Hepatocellular carcinoma (HCC), which comprises approximately 90% of cases of liver malignancy, is the third leading cause of cancer-related mortality worldwide [1] and is associated with diverse etiologic factors, such as hepatitis B and C viral infection, chronic alcohol intake, and exposure to a variety of dietary and environmental chemical carcinogens [2]
To investigate the role of Nrf2 in liver tumorigenesis, we compared the development of HCC in WT and Nrf2 KO mice
These results indicate that deletion of Nrf2 confers resistance to DEN-induced hepatocarcinogenesis in mice
Summary
Hepatocellular carcinoma (HCC), which comprises approximately 90% of cases of liver malignancy, is the third leading cause of cancer-related mortality worldwide [1] and is associated with diverse etiologic factors, such as hepatitis B and C viral infection, chronic alcohol intake, and exposure to a variety of dietary and environmental chemical carcinogens [2]. Recent progress in genomic analyses allows identification of several critical driver mutations and activating signaling pathways involved in HCC development [3, 4]. Somatic mutations in nuclear factor-erythroid 2-related factor 2 (Nrf, known as Nfe2l2) were noticed through whole-genome sequencing of HCC patients [1, 3]. Nrf was first characterized as a transcriptional activator that binds to a tandem repeat sequence named NF-E2 sequence Itoh and colleagues recognized the similarity between the NF-E2 binding sequence and the antioxidant response element sequence (ARE, 50-GCNNNG/CTCA-30; N: A/T/C/G), which is identified
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