Nuclear receptor CAR-mediated liver cancer and its species differences

ABSTRACT

Introduction: The nuclear receptor CAR plays an important role in the regulation of hepatic responses to xenobiotic exposure, including the induction of hepatocyte proliferation and chemical carcinogenesis. Phenobarbital, a well-known liver cancer promoter, has been found to promote hepatocyte proliferation via CAR activation. However, the molecular mechanisms by which CAR induces liver carcinogenesis remain unknown. In addition, it is believed that CAR-mediated liver carcinogenesis shows a species difference; phenobarbital treatment induces hepatocyte proliferation and liver cancer in rodents but not in humans. However, the mechanisms are also unknown.

Areas covered: Several reports indicate that the key oncogenic signaling pathways Wnt/β-catenin and Hippo/YAP are involved in CAR-mediated liver carcinogenesis. We introduce current data about the possible molecular mechanisms involved in CAR-mediated liver carcinogenesis and species differences by focusing on these two signaling pathways.

Expert opinion: CAR may activate both the Wnt/β-catenin and Hippo/YAP signaling pathways. The synergistic activation of both signaling pathways seems to be important for CAR-mediated liver cancer development. Low homology between the ligand binding domains of human CAR and rodent CAR might cause species differences in the interactions with proteins that control the Wnt/β-catenin and Hippo/YAP pathways as well as liver cancer induction.

KEYWORDS:

• CAR
• chemical carcinogenesis
• hepatocyte proliferation
• liver cancer
• nuclear receptor
• phenobarbital
• species difference

Article Highlights

• CAR activation in rodents causes hepatocyte proliferation and liver cancer, but the mechanisms remain unknown.

• The Wnt/β-catenin and Hippo/YAP signaling pathways are activated by CAR activation.

• The activation of both the Wnt/β-catenin and Hippo/YAP signaling pathways is important for CAR-dependent liver cancer.

• There is a clear species difference between humans and rodents for CAR-dependent liver cancer, as CAR activation induces liver cancer in rodents but not in humans.

• CAR may interact with proteins that regulate the Wnt/β-catenin and Hippo/YAP signaling pathways through its ligand binding domain, and the species difference in this protein-protein interaction might result in the species difference in CAR-mediated liver cancer.

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Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or a financial conflict regarding the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, granted or pending patents, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.