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.

中文翻译：

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核受体CAR介导的肝癌及其种属特异性差异

摘要 介绍：核受体 CAR 在调节肝脏对异物暴露的反应中起重要作用，包括诱导肝细胞增殖和化学致癌作用。苯巴比妥是一种众所周知的肝癌促进剂，已被发现通过 CAR 激活促进肝细胞增殖。然而，CAR诱导肝癌发生的分子机制仍然未知。此外，认为CAR介导的肝癌发生存在种属差异；苯巴比妥治疗诱导啮齿动物的肝细胞增殖和肝癌，但不会在人类中诱导。然而，其机制也是未知的。涵盖领域：一些报告表明，关键的致癌信号通路 Wnt/β-catenin 和 Hippo/YAP 参与了 CAR 介导的肝癌发生。我们通过关注这两种信号通路来介绍有关 CAR 介导的肝癌发生和物种差异的可能分子机制的当前数据。专家意见：CAR 可能同时激活 Wnt/β-catenin 和 Hippo/YAP 信号通路。两种信号通路的协同激活似乎对 CAR 介导的肝癌发展很重要。人类 CAR 和啮齿动物 CAR 的配体结合域之间的低同源性可能会导致与控制 Wnt/β-catenin 和 Hippo/YAP 通路的蛋白质相互作用以及肝癌诱导的物种差异。CAR 可以激活 Wnt/β-catenin 和 Hippo/YAP 信号通路。两种信号通路的协同激活似乎对 CAR 介导的肝癌发展很重要。人类 CAR 和啮齿动物 CAR 的配体结合域之间的低同源性可能会导致与控制 Wnt/β-catenin 和 Hippo/YAP 通路的蛋白质相互作用以及肝癌诱导的物种差异。CAR 可以激活 Wnt/β-catenin 和 Hippo/YAP 信号通路。两种信号通路的协同激活似乎对 CAR 介导的肝癌发展很重要。人类 CAR 和啮齿动物 CAR 的配体结合域之间的低同源性可能会导致与控制 Wnt/β-catenin 和 Hippo/YAP 通路的蛋白质相互作用以及肝癌诱导的物种差异。