响应Hif-1的IFFL解释了癌症中对循环缺氧的特定转录反应
Xihua Qiu1, Yamin Liu2, Paola Vera-Licona3
1Department of Biomedical Engineering, Univeristy of Connecticut, Storrs, CT, USA.
NPJ systems biology and applications
|November 25, 2025
概括
癌细胞通过使用基因电路通过缺氧诱导因子1 (HIF-1) 适应不稳定的氧气水平. 这些电路,特别是不连贯的前循环 (IFFL),驱动与乳腺癌进展相关的独特基因表达模式.
科学领域:
- 分子生物学分子生物学
- 癌症生物学 癌症生物学
- 系统生物学 系统生物学
背景情况:
- 固体瘤的特征是缺氧,这是一个关键的微环境因素.
- 缺氧诱导因子1 (HIF-1) 调节癌细胞适应缺氧.
- 瘤的氧气水平是动态的,通常表现为不稳定或循环缺氧,这会影响癌症表型.
研究的目的:
- 模拟基因调节回路,特别是不连贯的前循环 (IFFL),解释循环缺氧特异性基因转录.
- 为了研究IFFL如何解释循环HIF-1活动不同于稳定缺氧.
- 识别癌症进展中的HIF-1介导的IFFL信号中间体和实验证据.
主要方法:
- 转录组分析以比较基因表达在稳定和循环缺氧条件下.
- 基因调节电路的数学建模,专注于IFFLs.
- 使用p53和Notch1.1进行HIF-1形成IFFL的实验验证.
主要成果:
- 大多数基因对循环缺氧呈现平均反应,但部分基因表现出独特的振荡模式.
- IFFL模型展示了允许振荡特异转录的参数模式.
- IFFL电路可以产生更极端的基因表达比normoxia或稳定缺氧,由动态或平均缺氧信号的影响.
- 实验证据支持HIF-1与p53和Notch1形成IFFL,与乳腺癌进展有关.
结论:
- 基因调节回路,特别是IFFLs,提供了一个解释瘤微环境中的时间波动的机制.
- 循环缺氧可以通过非线性IFFL动态诱导特定的基因表达模式.
- 涉及p53和Notch1的HIF-1介导IFFL与乳腺癌进展和不良预后有关,突出显示瘤异质性的HIF-1驱动机制.
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