通过AEP分离的DDX3X诱导了替代RNA拼接事件,以调节癌细胞在恶劣的微环境中的适应
Wenrui Zhang1,2, Lu Cao3, Jian Yang4
1Brain Injury Center, Shanghai Institute of Head Trauma and.
The Journal of clinical investigation
|November 21, 2023
概括
癌细胞通过分裂DDX3X来适应低氧和营养,从而改变RNA拼接. 这一由阿斯巴拉金内酶 (AEP) 驱动的过程促进瘤生长,并预测患者的预后不佳.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 在RNA分离过程中.
背景情况:
- 固体瘤经常经历氧气和营养缺乏.
- 异常替代拼接 (AS) 驱动瘤进展,但其在恶劣的瘤微环境中的调节尚不清楚.
研究的目的:
- 阐明AS在癌细胞适应缺氧和营养缺乏的调节机制.
- 在压力条件下识别参与瘤恶性瘤的新型分子参与者和途径.
主要方法:
- 研究了由阿斯巴拉金内酶 (AEP) 以HIF1A依赖的方式诱导的DDX3X的缺氧和营养缺乏引起的裂变.
- 分析了截断的DDX3X (tDDX3X-C) 的核转位和拼接因子复合.
- 使用了体外试验,质母细胞瘤器官和动物模型来评估AEP/tDDX3X-C在瘤进展和患者预后中的作用.
主要成果:
- AEP将DDX3X分裂为tDDX3X-C,后者在核中聚集并诱导异常的AS事件,例如PRDM2.2中的外子跳跃.
- 通过这个过程生成的ARRB1-Δexon 13异型,调节糖解.
- AEP/tDDX3X-C和ARRB1-Δexon 13促进瘤恶性并与患者预后不佳有关.
结论:
- 发现了一种新的机制,即AEP分离的DDX3X触发了替代RNA拼接变化,使癌细胞能够适应营养和氧气短缺.
- 确定了AEP/tDDX3X-C作为瘤适应和恶性病的关键调节剂.
- 突出了固体瘤的潜在诊断和治疗点.
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