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乳糖驱动的IGF2BP3-介导的血清代谢重编程和RNA m6A-修改促进了HCC中的伦瓦替尼抗性

Yuanxiang Lu^1,2,3, Jinghan Zhu^1,3, Yuxin Zhang^1,3

¹Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

|October 25, 2024

概括

肝细胞癌 (HCC) 的代谢变化通过改变蛋白质乳酸和mRNA甲基化来驱动对lenvatinib治疗的耐药性. 针对这些代谢途径,特别是IGF2BP3,可以恢复对伦瓦替尼治疗的敏感性.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
代谢研究研究代谢研究

背景情况:

获得对分子向治疗的耐药性是治疗晚期肝细胞癌 (HCC) 的一个主要挑战.
代谢适应和表观遗传改造是癌症的关键特征,可能推动这种抗性.
伦瓦提尼布是一种用于HCC的向治疗,但耐药性往往会发展.

研究的目的:

研究在HCC. lenvatinib耐药性背后的机制.
探索新陈代谢重编程和表观遗传修饰在赋予耐药性的相互作用.
确定潜在的治疗策略,以克服伦瓦替尼布耐药性.

主要方法:

使用了抗伦瓦替尼布的HCC模型.
分析了代谢变化,包括糖解和血清代谢.
研究了关键基因 (PCK2,NRF2) 的蛋白质乳化 (特别是IGF2BP3) 和mRNA甲基化 (m6A).
在体内使用RNA干扰 (siRNA) 和糖解抑制剂 (2-DG).

主要成果:

增加的葡萄糖溶解导致乳酸积累和IGF2BP3乳化在耐药HCC.
乳基化IGF2BP3捕获PCK2和NRF2mRNA,增强它们的表达和重编程血清代谢.
改变的血清代谢增加了S-adenosylmethionine (SAM) 的可用性,用于PCK2和NRF2mRNAs的m6A甲基化.
一个涉及IGF2BP3,PCK2,SAM和m6A的反循环维持了PCK2/NRF2水平的升高,促进了耐药性.
用IGF2BP3-向siRNA或2-DG治疗恢复了伦瓦替尼的敏感性.

结论:

代谢重编程和表观遗传调节相互关联,在HCC中驱动伦瓦替尼布耐药性.
IGF2BP3-PCK2-SAM-m6A轴对于保持PCK2和NRF2的升高水平至关重要,增强抗氧化系统并促进耐药性.
准代谢途径,如糖解和特定蛋白质的修改,提供了一个有希望的战略,以克服在HCC. lenvatinib耐药性.

关键词:

在IGF2BP3乳化过程中.在PCK2中使用PCK2.葡萄糖溶解是什么伦瓦提尼布耐药性伦瓦提尼布耐药性血清蛋白代谢的代谢

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