肝癌干细胞（LCSC）显着影响肝癌的化疗耐药性和复发。已知多巴胺受体 D4 (DRD4) 会增强胶质母细胞瘤中的癌症干细胞 (CSC) 表型，并与一些非中枢神经系统肿瘤的不良预后相关；为了研究DRD4在LCSCs和非LCSCs中的基因和蛋白表达谱，我们利用转录组测序和Western blotting分析。采用生物信息学分析和免疫组化评估DRD4表达水平与肝癌患者病理特征的相关性。使用药理学或基因编辑技术探索 DRD4 对 LCSC 表型和信号通路的影响。此外，使用蛋白质印迹和免疫荧光检查了 DRD4 对 β-连环蛋白的蛋白表达和细胞内定位的影响。DRD4 表达在 LCSC 中显着升高，并且与肝癌的短生存期相关。 DRD4的表达和活性与HCC的耐药性、自我更新和致瘤性呈正相关。从机制上讲，DRD4通过激活PI3K/Akt/GSK-3β途径稳定β-catenin并促进其进入细胞核，从而增强LCSC表型。抑制DRD4表达和激活为根除LCSC和缓解化疗耐药提供了一种有前途的靶向治疗。 © 2024。作者获得施普林格自然有限公司的独家许可。

Liver cancer stem cells (LCSCs) significantly impact chemo-resistance and recurrence in liver cancer. Dopamine receptor D4 (DRD4) is known to enhance the cancer stem cell (CSC) phenotype in glioblastoma and correlates with poor prognosis in some non-central nervous system tumors; however, its influence on LCSCs remains uncertain.To investigate the gene and protein expression profiles of DRD4 in LCSCs and non-LCSCs, we utilized transcriptome sequencing and Western blotting analysis. Bioinformatics analysis and immunohistochemistry were employed to assess the correlation between DRD4 expression levels and the pathological characteristics of liver cancer patients. The impact of DRD4 on LCSC phenotypes and signaling pathways were explored using pharmacological or gene-editing techniques. Additionally, the effect of DRD4 on the protein expression and intracellular localization of β-catenin were examined using Western blotting and immunofluorescence.DRD4 expression is significantly elevated in LCSCs and correlates with short survival in liver cancer. The expression and activity of DRD4 are positive to resistance, self renewal and tumorigenicity in HCC. Mechanistically, DRD4 stabilizes β-catenin and promotes its entry into the nucleus via activating the PI3K/Akt/GSK-3β pathway, thereby enhancing LCSC phenotypes.Inhibiting DRD4 expression and activation offers a promising targeted therapy for eradicating LCSCs and relieve chemo-resistance.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.