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Review
. 2020 Oct 12;12(10):2932.
doi: 10.3390/cancers12102932.

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases

Claudia Orrù  1   2 , Silvia Giordano  1   2 , Amedeo Columbano  3
Affiliations
Review

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases

Claudia Orrù et al. Cancers (Basel). .

Abstract

Activation of the Keap1/Nrf2 pathway, the most important cell defense signal, triggered to neutralize the harmful effects of electrophilic and oxidative stress, plays a crucial role in cell survival. Therefore, its ability to attenuate acute and chronic liver damage, where oxidative stress represents the key player, is not surprising. On the other hand, while Nrf2 promotes proliferation in cancer cells, its role in non-neoplastic hepatocytes is a matter of debate. Another topic of uncertainty concerns the nature of the mechanisms of Nrf2 activation in hepatocarcinogenesis. Indeed, it remains unclear what is the main mechanism behind the sustained activation of the Keap1/Nrf2 pathway in hepatocarcinogenesis. This raises doubts about the best strategies to therapeutically target this pathway. In this review, we will analyze and discuss our present knowledge concerning the role of Nrf2 in hepatic physiology and pathology, including hepatocellular carcinoma. In particular, we will critically examine and discuss some findings originating from animal models that raise questions that still need to be adequately answered.

Keywords: Keap1/Nrf2 pathway; acute and chronic liver injury; liver regeneration; multistep hepatocarcinogenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Nrf2 activation in non-neoplastic liver physiopathology. This scheme illustrates the role of the Keap1/Nrf2 pathway in non-neoplastic liver. For details see text. Green lines indicate inhibition; the red arrow indicates stimulation. Contradictory results are indicated by question marks.
Figure 2
Figure 2
Schematic representation illustrating the opposite effects of Nrf2 activation on normal and carcinogen-initiated hepatocytes. Nrf2 inducers could lead to a more efficient repair of liver injury following administration of most necrogenic agents, including chemical carcinogens. On the other hand, Nrf2 inhibitors could promote reactive oxygen species (ROS)-induced injury, leading to death of preneoplastic cells, thus interfering with their progression to hepatocellular carcinoma (HCC). formula image stress promoting stimuli.
Figure 3
Figure 3
Distinct mechanisms leading to Nrf2 activation in cancer cells. The figure illustrates some of the best known mechanisms leading to the activation of the Keap1/Nrf2 pathway. Details are illustrated in the text. In the center of the figure is depicted an unstressed condition, where Nrf2 is bound to Keap1 and targeted to proteasomal degradation; nuclear translocation cannot thus take place. Numbers in brackets indicate the paragraph where the mechanism is described.
Figure 4
Figure 4
Schematic representation illustrating the possibility that distinct mechanisms of Nrf2 mutation occur at different stages of hepatocarcinogenesis. While in rat models [119] a high frequency of Nrf2 gene mutations occurred in early preneoplastic lesions, their incidence diminished with the progression to malignancy, concomitantly with p62 accumulation, suggesting that activation of the Keap1/Nrf2 pathway at late stages is mainly due to Keap1 sequestration by p62.
Figure 5
Figure 5
Dual role of Nrf2 in cancer.
See this image and copyright information in PMC

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