BMAL1-HIF2α异构体有助于ccRCCCC的发生
Rebecca M Mello1,2, Diego Gomez Ceballos1,2, Colby R Sandate3
1Department of Molecular and Cellular Biology, Scripps Research Institute, La Jolla, CA, 92037, USA.
Research square
|July 29, 2024
概括
清细胞细胞癌 (ccRCC) 细胞利用昼夜基因BMAL1驱动瘤生长. 向BMAL1-HIF2α可能通过增强药物敏感性为ccRCC提供新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 时间生物学 时间生物学
背景情况:
- 循环节障碍与癌症风险增加有关.
- 瘤往往表现出被破坏的昼夜基因表达.
- 清细胞细胞癌 (ccRCC) 显示出强大的节律基因表达.
研究的目的:
- 调查昼夜基因BMAL1在ccRCC中的作用.
- 在ccRCC中确定BMAL1和HIF2α之间的相互作用.
- 评估向BMAL1-HIF2α通路的治疗潜力.
主要方法:
- 在ccRCC组织和细胞系中分析基因表达.
- 通过CRISPR介导的BMAL1.1的耗尽.
- 染色体免疫沉测定. 染色体免疫沉测定.
- 评估ccRCC细胞在体外和体内移植的成长.
- 使用HIF2α抗剂 (PT2399) 的药物敏感性测定.
主要成果:
- 与健康脏相比,ccRCC中BMAL1的表达率较高.
- BMAL1与HIF2α形成一个功能性异构体,调节HIF2α基因的一个子集.
- 减少BMAL1减少了ccRCC的生长,并重新编程HIF2α活动.
- 较高的BMAL1水平与对HIF2α抗剂的敏感性相关.
- 对于PT2399,BMAL1-HIF2α复合体比ARNT-HIF2α复合体更敏感.
结论:
- 一种替代的BMAL1-HIF2α复合体有助于ccRCC生长和HIF2α活动.
- 在ccRCC中,BMAL1-HIF2α是潜在的治疗点.
- 向BMAL1可以使ccRCC细胞对HIF2α抗药物敏感.
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