击败YAP1降低YTHDF3以稳定SMAD7,从而抑制膀癌干细胞干细胞
Dandan Qiu1, Lingling Gao2, Xingwei Yu1
1Department of Urology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), 310000 Hangzhou, Zhejiang, China.
在膀癌干细胞 (BCSCs) 中的Yes关联蛋白1 (YAP1) 沉默抑制了含有YTH域的家族蛋白3 (YTHDF3) 介导的m6A改性SMAD7的降解. 这导致细胞干细胞减少和瘤进展.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症干细胞研究研究
背景情况:
- 之前的研究确定了Yes相关蛋白1 (YAP1) 在膀癌 (BLCA) 中的致癌作用.
- 这项研究研究了YAP1对膀癌干细胞 (BCSCs) 的特定影响及其潜在的分子机制.
研究的目的:
- 阐明YAP1在调节膀癌干细胞 (BCSCs) 的干细胞和进展中的作用.
- 确定分子途径,包括N6-甲基氨酸 (m6A) 修饰和蛋白质相互作用,参与YAP1在BCSC中的功能.
主要方法:
- 膀癌干细胞 (BCSCs) 被隔离并以CD133表达为特征.
- 生物信息分析确定了YAP1相互作用蛋白和SMAD7.7上的m6A位点.
- 实验涉及基因沉默 (YAP1),过度表达 (YTHDF3) 和分子测定 (MeRIP,RIP,qRT-PCR,西斑) 来评估基因表达,蛋白质相互作用和m6A修饰水平.
- 功能分析包括扩散 (BrdU),迁移/入侵 (Transwell) 和瘤球形成分析.
主要成果:
- 与父母的BLCA细胞相比,BCSCs表现出更高的干细胞标志物,YAP1,YTHDF3,TGF-β1表达,以及增强的入侵能力,SMAD7表达较低.
- YAP1敲击降低了SMAD7 m6A水平和YTHDF3-SMAD7的相互作用.
- 沉默YAP1抑制了BCSC的扩散,迁移,入侵和瘤球体的形成,同时增加了SMAD7的表达. 由于YTHDF3过度表达,这种效应被逆转了.
结论:
- YAP1在维持膀癌干的过程中起着至关重要的作用.
- YAP1沉默破坏了m6A修饰的SMAD7的YTHDF3介导的降解,从而降低了BCSC的干度和瘤进展的潜力.
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