中性粒细胞衍生的血清蛋白酶诱导FOXA2介导的自功能障碍,并通过蛋白酶激活受体2恶化结肠炎相关的癌症发生
Junhu Yuan1, Jianhui Ma1, Fanyu Zhang1
1State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Autophagy
|April 10, 2025
概括
肠道细胞中的F2RL1/PAR2缺乏通过损害自而使结肠炎相关的结肠直肠癌恶化. 中性粒细胞蛋白酶使这种途径失活,促进癌症的进展.
科学领域:
- 胃肠病学 胃肠病学
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
背景情况:
- 自在结肠炎相关的结肠直肠癌 (CAC) 中至关重要.
- 在炎症期间自流的非自主调节还未得到研究.
- F2RL1/PAR2信号在肠道平衡和CAC中的作用尚不清楚.
研究的目的:
- 调查F2RL1/PAR2在CAC中的肠上皮细胞 (IEC) 中的作用.
- 阐明在炎症期间由F2RL1/PAR2调节自的机制.
- 为了确定CAC的治疗点.
主要方法:
- 氧甲-德克斯硫酸盐 (AOM-DSS) 诱导的CAC模型在IECs中的F2rl1缺乏的小鼠中.
- 对自标记物的分析 (SQSTM1/p62,LC3),溶酶体酸化和DNA损伤.
- 在体外和体外的救援实验中使用FOXA2或ATP6V0E1过度表达.
- 研究中性粒细胞蛋白酶对F2RL1/PAR2信号传输的影响.
- 人类性结肠炎和结直肠癌样本的相关性分析.
主要成果:
- F2RL1/PAR2缺乏症加重了AOM-DSS诱导的CAC,增加了瘤负担.
- 缺陷促进了自功能障碍,其特征是SQSTM1/p62积累和抑制了自细胞-溶酶体融合.
- 通过抑制FOXA2诱导的ATP6V0E1转录,溶酶体酸性减少.
- 过度表达FOXA2或ATP6V0E1挽救了自,减少了活性氧物种 (ROS) 和DNA损伤.
- 中性粒细胞蛋白酶抑制FOXA2,导致自功能障碍,这种效果被F2RL1淘汰阻止.
- 在人类IBD和CRC中,F2RL1/PAR2信号传递和FOXA2-ATP6V0E1活性与相关.
结论:
- 在IECs中的F2RL1缺陷通过抑制FOXA2损害了V-ATPase介导的自,加剧了CAC.
- 中性粒细胞通过蛋白酶使F2RL1/PAR2信号失活,从而导致自功能受损,从而对CAC作出贡献.
- 通过自,F2RL1/PAR2信号传递对肠道平静至关重要.
- 准F2RL1/PAR2和中性粒细胞蛋白酶为CAC提供了潜在的治疗策略.
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