Abstract
NF-E2-related factor 2 (NRF2) is a basic leucine zipper transcription factor, a master regulator of redox homeostasis regulating a variety of genes for antioxidant and detoxification enzymes. NRF2 was, therefore, initially thought to protect the liver from oxidative stress. Recent studies, however, have revealed that mutations in NRF2 cause aberrant accumulation of NRF2 in the nucleus and exert the upregulation of NRF2 target genes. Moreover, among all molecular changes in hepatocellular carcinoma (HCC), NRF2 activation has been revealed as a more prominent pathway contributing to the progression of precancerous lesions to malignancy. Nevertheless, how its activation leads to poor prognosis in HCC patients remains unclear. In this review, we provide an overview of how aberrant activation of NRF2 triggers HCC development. We also summarize the emerging roles of other NRF family members in liver cancer development.
Highlights
Liver cancer is one of the most troublesome human malignancies, with an annual incidence of around 600,000 worldwide
NF-E2-related factor 2 (NRF2) transcription factor is activated by oxidative stress, and recent studies have suggested that the aberrant activation of NRF2 triggers hepatomegaly and hepatocellular carcinoma (HCC) development [13,14], this factor acts to protect the liver from oxidative stress
Constitutively activated NRF2 signaling in Keap1-KD mice fed a high-fat diet (HFD) exhibited greater lipogenic gene expression, inflammation, and increased hepatic steatosis [122]. These findings suggest that aberrant activation of NRF2 helps to trigger development of non-alcoholic steatohepatitis (NASH) or Non-alcoholic fatty liver disease (NAFLD), gain-of-function type mutations in NRF2 may initiate the development of HCC by inducing NASH or NAFLD
Summary
Infection with HBV or HCV and alcohol-induced hepatocarcinogenesis are associated with oxidative stress in the liver [1,2,3,4,5]. Oxidative stress has been suggested to cause cancer-specific gene mutations in the cell cycle, apoptosis, and various processes of the regeneration cycle, which may lead to liver damage [9,10,11,12]. NF-E2-related factor 2 (NRF2) transcription factor is activated by oxidative stress, and recent studies have suggested that the aberrant activation of NRF2 triggers hepatomegaly and HCC development [13,14], this factor acts to protect the liver from oxidative stress. We describe how the aberrant transcriptional activation of NRF2 caused by its nuclear accumulation may develop HCC at molecular level
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