Constitutive androstane receptor (CAR) functions as a tumor suppressor via regulating stemness in liver cancer

Constitutive androstane receptor (CAR) is a xenosensor that is almost exclusively expressed in the liver. Studies in rodents suggest an oncogenic role for CAR in liver cancer, but its role in human liver cancer is unclear. We aimed to investigate the functional roles of CAR in human liver cancer with a focus on the liver cancer stem cells. We used bioinformatics to increase our understanding of CAR in human liver cancer and associated stem cell markers. We studied the functional roles of CAR in human liver cancer with a focus on the liver cancer stem cell using siRNA, modulation of CAR activity, and tumorsphere formation assays. We have revealed significant associations between CAR and a wide variety of signalling pathways including stemness signalling. Further in vitro studies have shown that activation of CAR significantly reduces cancer cell stemness and represses proliferation, migration, invasion, and the tumorsphere-forming abilities of liver cancer cells (p < 0.05). Our data demonstrates the unequivocal tumor-suppressive role of CAR in liver cancer. While more detailed mechanistic studies are warranted, the efficacy of CAR xeno-activators in the treatment of advanced hepatocellular carcinoma (HCC) may potentially open a new avenue for liver cancer therapy.