Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
Semin Liver Dis. 2024 Aug;44(3):383-393. doi: 10.1055/a-2349-7236. Epub 2024 Jun 20.
Liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the incidence of HCC is on the rise. Liver cancers in general and HCC in particular do not respond to chemotherapy. Radiological ablation, surgical resection, and liver transplantation are the only medical therapies currently available. Hepatocyte nuclear factor 4 α (HNF4α) is an orphan nuclear receptor expressed only in hepatocytes in the liver. HNF4α is considered the master regulator of hepatic differentiation because it regulates a significant number of genes involved in various liver-specific functions. In addition to maintaining hepatic differentiation, HNF4α also acts as a tumor suppressor by inhibiting hepatocyte proliferation by suppressing the expression of promitogenic genes and inhibiting epithelial to mesenchymal transition in hepatocytes. Loss of HNF4α expression and function is associated with rapid progression of chronic liver diseases that ultimately lead to liver cirrhosis and HCC, including metabolism-associated steatohepatitis, alcohol-associated liver disease, and hepatitis virus infection. This review summarizes the role of HNF4α in liver cancer pathogenesis and highlights its potential as a potential therapeutic target for HCC.
肝癌是全球第六大常见癌症，也是癌症相关死亡的第四大主要原因。肝细胞癌（HCC）是最常见的原发性肝癌，其发病率呈上升趋势。一般来说，肝癌，尤其是 HCC，对化疗没有反应。放射消融、手术切除和肝移植是目前仅有的几种医学治疗方法。肝细胞核因子 4α（HNF4α）是一种在肝脏中仅在肝细胞中表达的孤儿核受体。HNF4α 被认为是肝分化的主要调节因子，因为它调节了大量参与各种肝特异性功能的基因。除了维持肝分化外，HNF4α 还通过抑制促有丝分裂基因的表达和抑制肝细胞的上皮间质转化来抑制肝细 胞增殖，从而发挥肿瘤抑制因子的作用。HNF4α 表达和功能的丧失与慢性肝病的快速进展有关，最终导致肝硬化和 HCC，包括与代谢相关的脂肪性肝炎、酒精相关的肝病和肝炎病毒感染。本综述总结了 HNF4α 在肝癌发病机制中的作用，并强调了其作为 HCC 潜在治疗靶点的潜力。
