谷氨酸缺乏触发了Tribbles同类3依赖的G-四重复分辨率,以维持DNA修复和瘤存活
Qiang Ji1, Xuedan Sun2, Zhangran Sun1
1Translational Research Institute of Henan Provincial People's Hospital and School of Basic Medical Sciences, Henan University, Zhengzhou, China.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|March 7, 2026
概括
通过保护DNA,TRIB3蛋白有助于肝细胞癌 (HCC) 细胞在低谷氨胺的情况下生存. 针对TRIB3-DDX5-G4 DNA轴可能为HCC提供新的治疗方法.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 谷氨酸对瘤生长至关重要,但针对其新陈代谢的疗法面临阻力.
- 肝细胞癌 (HCC) 细胞表现出对谷氨酸缺乏的适应性抵抗力.
- 了解耐药机制对于开发有效的HCC治疗至关重要.
研究的目的:
- 确定在氨酸限制下HCC细胞中代谢适应的关键介质.
- 调查假酶TRIB3在细胞对谷氨缺乏的反应中的作用.
- 探索TRIB3-DDX5-G4 DNA轴作为HCC的潜在治疗点.
主要方法:
- 在缺乏谷氨胺的情况下,研究了HCC细胞中的TRIB3表达和功能.
- 使用了c-Jun淘汰和TRIB3/DDX5耗尽实验.
- 分析了DNA损伤,G-四重复DNA (G4-DNA) 结构和DNA损伤修复 (DDR) 途径.
- 在小鼠中使用HCC异种移植进行了体内研究,这些小鼠接受了缺乏谷氨胺的饮食.
- 与临床HCC患者数据相关的TRIB3表达.
主要成果:
- 在缺乏谷氨胺的情况下,TRIB3被上调,以保证DNA修复的忠实性.
- TRIB3和DDX5形成一个复合体,可以分解G4-DNA结构.
- TRIB3或DDX5的耗尽会增加G4-DNA的积累,DNA损伤,并抑制DDR通路,包括同源重组 (HR).
- TRIB3-DDX5 阻止了G4-DNA介导的BRCA1和RAD51AP1转录的抑制.
- TRIB3沉默抑制了HCC异种移植的生长,并在缺乏谷氨胺的情况下增加了细胞亡.
- 在HCC中,TRIB3过度表达,并与预后不佳有关.
结论:
- TRIB3-DDX5-G4 DNA轴是HCC中代谢适应和DNA修复的关键媒介.
- 这个轴代表了HCC和其他TRIB3高的癌症的有希望的治疗标.
- 向TRIB3可以克服针对谷氨胺代谢的治疗方法的耐药性.
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