瘤微环境中的NR1D1缺乏会通过激活NLRP3炎症酶激活肺瘤的发展
Sun Mi Kim1,2, Yoon Jeon3, Ji Yun Jang3,4
1Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi, 10408, Republic of Korea. ksm999@ncc.re.kr.
Cell death discovery
|July 31, 2023
概括
核受体Rev-erbα (NR1D1) 通过抑制NLRP3炎症酶,在肺癌中起到瘤抑制作用. NR1D1缺乏促进肺瘤发生,这表明NLRP3炎症酶阻断作为治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 循环节生物学 日间生物
背景情况:
- 核受体Rev-erbα (NR1D1) 是一个重要的昼夜时钟调节器.
- 它在癌症,特别是肺癌的发展中的作用仍然在很大程度上未被探索.
- 循环时钟失调与各种癌症有关.
研究的目的:
- 为了研究NR1D1在肺部瘤发生中的作用.
- 阐明涉及瘤微环境和炎症酶激活的潜在机制.
- 探索针对NR1D1和NLRP3炎症酶的潜在治疗策略.
主要方法:
- 利用基因工程小鼠模型研究Nr1d1在肺癌中.
- 在实验室中评估NR1D1对非小细胞肺癌 (NSCLC) 细胞增殖的影响.
- 通过 ортотоп模型研究NR1D1对瘤微环境的影响.
- 分析了NACHT,LRR和PYD域含蛋白3 (NLRP3) 炎症酶激活.
- 评估了来自NR1D1缺陷巨细胞的条件介质对癌细胞的影响.
- 在临床前模型中测试了NLRP3炎症酶抑制剂MCC950的疗效.
主要成果:
- 瘤微环境中的NR1D1缺陷在一个正位体模型中加速了肺癌的发展.
- 缺乏NR1D1的小鼠表现出NLRP3炎症酶激活的增加.
- 来自NR1D1缺陷巨细胞的受条件介质促进了肺癌细胞的增殖和上皮-介质细胞转变 (EMT).
- 在NR1D1缺乏的小鼠中,MCC950治疗显著抑制了瘤发生,并在体外阻断了癌细胞的增殖和EMT.
结论:
- 在肺癌微环境中,NR1D1作为瘤抑制剂起作用.
- NR1D1对NLRP3炎症酶途径进行负调节.
- 通过NR1D1激活向NLRP3炎症酶,为肺癌治疗提供了潜在的治疗途径.
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