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.
bioRxiv : the preprint server for biology
|June 19, 2024
概括
清细胞细胞癌 (ccRCC) 细胞利用钟基因BMAL1驱动瘤生长. 向BMAL1-HIF2α可以提高对HIF2α抗药物的敏感性,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模式.
- 清细胞细胞癌 (ccRCC) 显示出强大的节律基因表达,BMAL1水平升高.
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之间的功能相互作用.
- 探索向BMAL1-HIF2α通路的治疗潜力.
主要方法:
- 对ccRCC和健康脏组织中的基因表达的分析.
- 使用细胞培养模型研究BMAL1和HIF2α之间的相互作用.
- 耗尽BMAL1并评估其对ccRCC细胞生长和基因表达的影响.
- 评估ccRCC异种移植对HIF2α抗剂的敏感性.
- 评估BMAL1水平对药物敏感性的影响.
主要成果:
- 与健康脏相比,在ccRCC中BMAL1的调节升高.
- 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,并改变了HIF2α染色体协会.
- 较高的BMAL1表达与对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复合物有助于ccRCC的生长和活动.
- 在ccRCC的发病过程中,BMAL1发挥着重要作用.
- 针对BMAL1-HIF2α相互作用可能是ccRCC的可行的治疗策略,提高对HIF2α抗剂的敏感性.
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