The oncogenic potential of Nrf2 in diethylnitrosamine-induced murine hepatocarcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths, and is phenotypically and genetically heterogeneous. Nuclear factor-erythroid 2-related factor 2 (Nrf2, also known as Nfe2l2) is a transcription factor that regulates the expression of a battery of genes encoding phase II carcinogen detoxifying enzymes and other cytoprotective proteins, hence being considered a prominent target for liver cancer chemoprevention. However, here I unexpectedly found that Nrf2 knockout mice resisted diethylnitrosamine (DEN)-induced hepatocarcinogenesis without impairment in either metabolic activation of DEN by cytochrome P450 2E1 (Cyp2e1) or hepatic vasculature. In the liver tumors, there was enhanced expression, nuclear translocation, and transcriptional activity of Nrf2. The overactivated Nrf2 was noticed to be required for hepatoma growth during DEN-induced murine HCC. Following DEN treatment, genetic disruption of Nrf2 led to a decrease in the expression levels of a transporter involved in glucose uptake and pentose phosphate pathway (PPP)-related enzymes, whose depletion is reportedly associated with amelioration of HCC. Of note, alterations in the domain binding to its endogenous inhibitor Kelch-like ECH-associated protein 1 (Keap1) likely accounted for the enhanced activity of Nrf2. Additionally, HCC patients bearing activating mutations in Nrf2 had shorter overall survival compared with their cohort. These findings suggest that Nrf2 is a bona fide liver cancer driver and could serve as a therapeutic target for HCC treatment.