向CREB结合蛋白 (CBP) 通过对C-MYC的表观遗传调节,取消结直肠癌的干性
Dai-Jung Chung1, Chun-Hao Wang1,2, Pin-Jung Liu1,3
1Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.
Cancer gene therapy
|October 2, 2024
概括
研究人员将人类诱导的多能干细胞 (hiPSC) 转化为结直肠癌干细胞 (CSC). 这一过程涉及C-MYC通过基因素乙化进行上调,提供了一种抑制CSC干性的新策略.
科学领域:
- 干细胞生物学 干细胞生物学
- 癌症研究 癌症研究
- 分子机制的分子机制
背景情况:
- 全球结肠直肠癌 (CRC) 的发病率正在上升.
- 癌症干细胞 (CSCs) 驱动CRC的进展,复发和转移.
- 调节结直肠CSC发展的机制尚未完全理解.
研究的目的:
- 从人类诱导的多能干细胞 (hiPSCs) 产生结直肠CSC.
- 调查大肠直肠CSC产生和干性的基础分子机制.
- 探索针对结肠直肠CSC的潜在治疗策略.
主要方法:
- 从CRC细胞中使用条件介质将hiPSC转化为癌症干细胞 (hiPSC-CSCs).
- 在小鼠模型中评估hiPSC-CSC特性,包括形态,标记物表达,瘤性和转移潜力.
- 对表皮细胞-介质细胞过渡 (EMT),C-MYC调节和基因素乙化进行分析.
- 研究CREB结合蛋白 (CBP) 和基因素脱乙酶 (HDAC) 在C-MYC激活中的作用.
- 对CBP的药理抑制和CRISPR/Cas9介导的废除,以评估其对茎状性的影响.
主要成果:
- hiPSCs成功地转化为hiPSC-CSCs,具有类似茎的特性和致瘤/转移能力.
- hiPSC-CSCs表现出EMT,促进了迁移和血管生成.
- 在hiPSC-CSC分化过程中,C-MYC被上调,由CBP与C-MYC促进体结合,HDAC解离和增加的基因素乙化调节.
- 抑制CBP显著降低了hiPSC-CSC的干度.
结论:
- 结肠直肠CSC可以从hiPSC生成,为CRC研究提供了一个新型模型.
- 通过CBP调节的基因组乙化对C-MYC的升调对于结直肠CSC的产生至关重要.
- 针对CBP是一种潜在的治疗策略,可以减轻结肠直肠CSC干.
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