Role of the constitutive androstane receptor (CAR) in human liver cancer

The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily (subfamily 1, group I, member 3, also known as NR1I3) that is almost exclusively expressed in the liver. CAR interacts with key signalling pathways such as those involved in drug, energy and bilirubin metabolism. In mouse models, activation of CAR leads to tumorigenesis by inducing pro-proliferative and anti-apoptotic signalling. However, many previous reports have shown species differences between CAR activity in animal models and humans. Recent studies have demonstrated that the mode of action of CAR in rodent liver tumorigenesis is not applicable to humans. Despite this, many studies still continue to study the role of CAR in animal models, hence, there is a need to further explore the role of CAR in human diseases particularly cancers. While there is limited evidence for a role of CAR in human cancers, some studies have proposed a tumour-suppressive role of CAR in liver cancer. In addition, recent studies exploring CAR in human livers demonstrated a hepato-protective role for CAR in and more specifically, its ability to drive differentiation and liver regeneration. This review will discuss the role of CAR in liver cancer, with a focus on species differences and its emerging, tumour-suppressive role in liver cancer and its role in the regulation of liver cancer stem cells.