多镇压复合体2结合并稳定NANOG以抑制与分化相关的基因,以促进自我更新
Da-Wei Yeh1, Cheng Liu1, Juan Carlos Hernandez1
1Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
iScience
|July 14, 2023
概括
酒精和型肝炎病毒 (HCV) 联合感染通过激活NANOG促进肝癌干细胞. 准PRC2-NANOG相互作用为肝细胞癌 (HCC) 提供了一个新的治疗策略.
科学领域:
- 肝细胞癌 (HCC) 病原发生
- 癌症干细胞生物学
- 分子瘤学分子瘤学
背景情况:
- 酒精和C型肝炎病毒 (HCV) 通过托尔类受体4 (TLR4) 信号传递协同促进肝细胞癌 (HCC).
- 作为一种多能转录因子,NANOG对于保持HCC中瘤发起细胞 (TICs) 的干性至关重要.
- 与PRC2复合的NANOG抑制氧化酸化 (OXPHOS) 基因表达,从而产生TICs.
研究的目的:
- 阐明酒精和HCV介导的HCC发展背后的分子机制.
- 调查NANOG的作用及其与PRC2复合体在ICT生成中的相互作用.
- 为了确定HCC治疗的新型治疗点.
主要方法:
- 研究了酒精和HCV对TLR4信号和NANOG激活的协同作用.
- 分析了NANOG,PRC2复合体 (EED,EZH2,SUZ12) 和PEST域之间的相互作用.
- 在人性化的FRG HCC小鼠模型中利用CRISPR-Cas9介导的ARID1A淘汰和CTNNB1突变.
- 评估了PRC2-NANOG接口抑制剂和FAO抑制剂在阻断瘤生长中的有效性.
主要成果:
- 酒精和HCV通过TLR4信号来协同激活NANOG,促进HCC干性.
- 纳诺基蛋白的稳定性由其PEST域与EED结合来调节,防止蛋白质体的降解.
- 人类ARID1A的损失通过减少线粒体ROS.赋予了对FAO和PRC2抑制的抵抗力.
- 通过CRISPR-Cas9介导的ARID1A淘汰和CTNNB1突变促进了HCC的发展.
- 抑制PRC2-NANOG相互作用或FAO有效地阻止了小鼠模型中的瘤生长.
结论:
- PRC2-NANOG相互作用是HCC干和瘤发展的关键驱动因素.
- 针对PRC2-NANOG相互作用是HCC的一种有前途的治疗策略.
- 诱导与分化相关的基因和破坏NANOG蛋白的稳定性可以抑制HCC的进展.
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