准Wnt3a和Loxl2协同诱导肝癌干细胞中的铁亡并抑制瘤发生
Guanghui Ren1, Qingwei Cong1, Jing Wang1
1Department of Infectious Disease, Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
Cancer science
|February 2, 2026
概括
在肝癌干细胞中准Wnt3a和Loxl2促进铁亡,显著抑制瘤生长. 双重敲除Wnt3a和Loxl2显示出最强的瘤抑制,突出了ZEB1的作用.
科学领域:
- 在瘤学瘤学.
- 细胞死亡机制 细胞死亡机制
- 分子生物学分子生物学
背景情况:
- 肝细胞癌 (HCC) 是一个重大的临床挑战,因为它的预后不佳和高死亡率.
- 铁亡是一种受调节的细胞死亡形式,在癌症的发展和治疗反应中起着至关重要的作用.
- Wnt信号传递和 lysyl氧化酶 (Lox) 家族成员正在成为关键调节者,涉及铁亡.
研究的目的:
- 研究Wnt3a和/或Loxl2对肝癌干细胞 (LCSCs) 和小鼠的正型瘤生长的影响.
- 在HCC中探索与ferroptosis相关的基因在Wnt3a/Loxl2调节的背景下参与ferroptosis.
- 确定关键的调节因素,如ZEB1,参与Wnt3a/Loxl2介导的铁和瘤抑制.
主要方法:
- 生物信息分析以确定与铁和HCC相关的差异表达基因 (DEG),与Wnt3a/Loxl2表达相关.
- 来自Hep3B细胞的LCSC中的lentiviral介导基因敲除,以评估铁亡标记物和DEG表达.
- 通过CRISPR-Cas9技术生成Wnt3a/Loxl2淘汰赛小鼠,用于建立正型瘤模型.
- 在细胞和动物模型中评估瘤抑制率,铁亡指标 (Fe2+,MDA,GSH) 和ZEB1表达.
主要成果:
- 生物信息学在HCC中确定了199个与铁化相关的DEG,其中ZEB1通过蛋白质-蛋白质相互作用 (PPI) 分析被确定为关键基因.
- Wnt3a/Loxl2 Knockdown显著改变了铁亡标志物,增加了细胞内铁 (Fe2+) 和MDA水平,同时降低了谷氨 (GSH),在双击细胞中影响最为明显.
- 在单击和双击的小鼠模型中,正管瘤生长被实质性地抑制,其抑制率分别为51%,71%和93%.
- 来自淘汰赛模型的瘤组织显示了与细胞发现一致的铁亡标记物的变化,并且ZEB1表达被上调.
结论:
- 击败Wnt3a和/或Loxl2有效地促进LCSCs中的铁亡,从而显著抑制了正管瘤生长.
- 双击Wnt3a和Loxl2显示出最强的抗瘤作用,强调了这些途径的协同作用.
- ZEB1成为Wnt3a/Loxl2介导的铁亡途径的关键调节因子,为HCC.提供了潜在的治疗标.
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