在MAPK12促销器上的G-四重复结构动态决定了转录切换以确定乳腺癌的干性
Pallabi Sengupta1, Anindya Dutta1, Y V Suseela2
1Department of Biological Sciences, Unified Academic Campus, Bose Institute, EN-80, Sector V, Salt Lake, Bidhan Nagar, Kolkata, West Bengal, 700091, India.
Cellular and molecular life sciences : CMLS
|January 12, 2024
概括
三阴性乳腺癌 (TNBC) 涉及MAPK12,它驱动癌症干细胞扩张. 通过像TGS24这样的化合物准MAPK12-G4结构来抑制转录,减少TNBC的干细胞和转移.
科学领域:
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
- 癌症研究 癌症研究
背景情况:
- P38γ (MAPK12) 在三阴性乳腺癌 (TNBC) 中高度表达,促进癌症干细胞 (CSC) 扩张和转移.
- 在MAPK12促进体中富含G的序列表明G-四重复 (G4) 形成的潜力可以逆转瘤发生,尽管这一点仍未得到证实.
研究的目的:
- 研究TNBC中MAPK12促进体G4结构的形成和功能.
- 探索针对MAPK12-G4结构用于TNBC治疗的治疗潜力.
主要方法:
- 在MAPK12促进体上游的相邻G4基因的识别和它们平行G4结构的特征.
- 使用CRISPR-Cas9删除G4基因,并合成纳二胺 (NDI) 衍生物 (TGS24) 用于高亲和度G4结合.
- RNA测序分析以阐明NDI诱导的G4介导的转录调节的分子机制.
主要成果:
- 在MAPK12促进体中确定了形成平行G4结构的两个相邻的G4动机,它们与由Sp1和Nucleolin调节的双重DNA处于平衡状态.
- 删除G4动机和TGS24处理通过干扰转录因子招募来抑制MAPK12转录.
- 抑制MAPK12-G4降低了瘤性RAS转化,NANOG转激活和CD44高/CD24低群体,从而阻止了CSC的茎状性质.
结论:
- 在MAPK12促进体内,有功能G4结构,调节MAPK12转录和TNBC干性.
- 针对MAPK12-G4结构使用NDI衍生品,如TGS24,通过抑制CSC扩张和转移,为TNBC提供了一个有希望的治疗策略.
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