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瘤性NRF2和野生型HRAS之间的合作促进了乳腺癌的进展

Su-Jung Kim¹, Soma Saeidi¹, Nam-Chul Cho²

¹Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.

Cellular signalling

|June 5, 2025

概括

过度表达的野生型HRAS (HRAS^WT) 通过稳定NRF2和促进NRF2-STAT3相互作用来驱动侵略性乳腺癌. 这一途径,特别是在三阴性乳腺癌 (TNBC) 中,提供了一个潜在的治疗点.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
遗传学是一个遗传学.

背景情况:

在乳腺癌中,HRAS经常过度激活,但突变并不常见.
野生型HRAS (HRAS^WT) 过度表达,而不是突变,与三阴性乳腺癌 (TNBC) 等侵袭性乳腺癌亚型有关.

研究的目的:

阐明过度表达的野生型HRAS (HRAS^WT) 在人类乳腺癌进展中的致癌作用.
研究HRAS^WT促进TNBC攻击性的分子机制.

主要方法:

定量PCR (qPCR) 用于评估HRAS^WT表达在不同的乳腺癌亚型.
同免疫沉试验用于研究HRAS和NRF2相互作用.
对瘤组织中NRF2-STAT3复合体形成的分析.
RNA测序以识别下游基因表达变化.
基因沉默实验 (NRF2和STAT3的敲除).

主要成果:

与光线乳腺瘤和正常组织相比,TNBC组织和细胞表现出显著更高的HRAS^WT表达.
HRAS^WT直接与NRF2相互作用并稳定NRF2,这种结合在KRAS没有观察到.
HRAS^WT诱导NRF2和STAT3之间的功能相互作用,特别是在TNBC中.
结合NRF2和STAT3的沉默明显抑制了TNBC细胞的生长,比单独的沉默更多.
RNA测序揭示了细胞迁移相关基因的改变表达,表明NRF2-STAT3的协同活性.

结论:

NRF2作为HRAS的下游效应器,独立于KEAP1调节信号.
非突变HRAS过度表达,与NRF2结合,驱动乳腺癌的进展.
HRAS-NRF2-STAT3轴代表了TNBC的潜在治疗目标.

关键词:

这就是NRF2的NRF2.没有突变的HRAS.复氧化平衡还原平衡.在STAT3中,我们可以使用STAT3.三阴性乳腺癌是三阴性乳腺癌.

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