代谢综合征通过核因子发展为心脏癌症-E2相关因子2-编程死亡-连接体1信号传递
Keisuke Kusano1, Kaname Uno2, Toru Tamahara3
1Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Cellular and molecular gastroenterology and hepatology
|September 11, 2025
概括
高脂肪饮食通过增加肠道细菌副产品脂聚糖 (LPS) 来促进胃癌,导致炎症和PD-L1表达. 准这种途径可能会改善癌症治疗抵抗力.
科学领域:
- 胃肠道学和瘤学
- 免疫学和新陈代谢
背景情况:
- 胃心脏腺癌 (GCA) 的发病率上升与代谢综合征 (MetS) 相似.
- 脂聚糖 (LPS) 涉及GCA发育和免疫检查点抑制剂耐药性.
研究的目的:
- 为了调查高脂肪饮食 (HFD) 诱导的内毒素是否促进GCA进展.
- 在这个过程中确定编程死亡连接体1 (PD-L1) 信号的作用.
主要方法:
- K19-Wnt1/C2mE小鼠被食HFD或对照饮食,有或没有LPS和克洛德罗纳酸脂质体 (CLs).
- 使用Nrf2缺乏的K19-Wnt1/C2mE小鼠来评估Nrf2在瘤发生中的作用.
- 实验涉及MKN7和THP-1细胞系,以阐明分子机制.
主要成果:
- HFD + LPS诱导的GCA进展,其特征是瘤扩散的增加,巨细胞透,肠道失生症,屏障损伤,内毒性,以及胰岛素抵抗.
- 在瘤中观察到8-OHdG,Nqo1,TNF-α,p-NFκB和PD-L1的升调;TNF-α存在于瘤细胞和巨细胞中.
- Nrf2 缺乏减少了瘤生长和PD-L1 表达,但没有解决肠道屏障损伤或内毒性;LPS刺激了TNF-α的产生和细胞系中的NFκB-PD-L1信号传递.
结论:
- 与HFD相关的代谢内毒症促进了GCA的进展.
- 这种促进通过PD-L1诱导发生在瘤细胞中,通过LPS.激活的Nrf2信号传递进行中介.
- 此外,LPS激活的巨细胞释放TNF-α,激活瘤微环境中的NFκB信号传递.
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