Bae Sarah Da Won, Nguyen Romario, Yuen Lawrence, Lam Vincent, George Jacob, Qiao Liang
Storr Liver Centre, Westmead Institute for Medical Research, Department of Medicine, the University of Sydney at Westmead Hospital, Westmead, NSW, 2145, Australia.
Department of Surgery, Westmead Hospital, Westmead, NSW, 2145, Australia.
Sci Rep. 2024 Dec 28;14(1):30926. doi: 10.1038/s41598-024-81571-z.
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.
组成型雄烷受体（CAR）是一种几乎仅在肝脏中表达的异源物质传感器。对啮齿动物的研究表明CAR在肝癌中具有致癌作用，但其在人类肝癌中的作用尚不清楚。我们旨在研究CAR在人类肝癌中的功能作用，重点关注肝癌干细胞。我们利用生物信息学来加深对人类肝癌中CAR及相关干细胞标志物的理解。我们使用小干扰RNA（siRNA）、调节CAR活性和肿瘤球形成试验，重点研究了CAR在人类肝癌干细胞中的功能作用。我们发现CAR与包括干性信号在内的多种信号通路之间存在显著关联。进一步的体外研究表明，CAR的激活显著降低癌细胞干性，并抑制肝癌细胞的增殖、迁移、侵袭和肿瘤球形成能力（p<0.05）。我们的数据证明了CAR在肝癌中明确的肿瘤抑制作用。虽然需要进行更详细的机制研究，但CAR异源激活剂在晚期肝细胞癌（HCC）治疗中的疗效可能为肝癌治疗开辟一条新途径。
