Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2

Abstract

The liver is a key metabolic organ that is essential for production of blood proteins, lipid and sugar metabolism and detoxification of naturally occurring and foreign harmful chemicals. To maintain its mass and many essential functions, the liver possesses remarkable regenerative capacity, but the latter also renders it highly susceptible to carcinogenesis. In fact, liver cancer often develops in the context of chronic liver injury. Currently, primary liver cancer is the second leading cause of cancer-related deaths, and as the rates of other cancers have been declining, the incidence of liver cancer continues to rise with an alarming rate. Although much remains to be accomplished in regards to liver cancer therapy, we have learned a great deal about the molecular etiology of the most common form of primary liver cancer, hepatocellular carcinoma (HCC). Much of this knowledge has been obtained from studies of mouse models, using either toxic chemicals, a combination of fatty foods and endoplasmic reticulum stress or chronic activation of specific metabolic pathways. Surprisingly, NRF2, a transcription factor that was initially thought to protect the liver from oxidative stress, was found to play a key role in promoting HCC pathogenesis.

Figure 1.

The cancer jackpot. In order for cancer to develop, a single tumor progenitor needs to accumulate multiple oncogenic mutations.

Figure 2.

HcPC isolation and the mechanism of autocrine IL-6. (A) HcPCs are collagenase-resistant aggregated cells isolated from livers of mice that are HCC bound. The collagenase-resistant cell aggregates are enriched in HcPCs and are more potent in forming HCC when transplanted into suitable host than non-aggregated hepatocytes. (B) LIN28 is upregulated in HcPCs leading to inhibited Let7 micro-RNAs, resulting in de-repression of autocrine IL-6 production, STAT3 activation and cell proliferation.

Figure 3.

The unexpected role of NRF2 in HCC development. Transient NRF2 activation suppresses carcinogenesis by upregulating the expression of antioxidant proteins that neutralize ROS and maintain protective amounts of reduced glutathione. However, chronic activation of NRF2 by p62 accumulation or KEAP1 and/or NRF2 mutations potentiates liver carcinogenesis by inhibiting oxidative stress induced senescence or death of initiated hepatocytes allowing these cells to accumulate numerous oncogenic mutations.