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.