胶质瘤
ABCA1
下调和上调
小胶质细胞
胆固醇
癌症研究
生物
异柠檬酸脱氢酶
载脂蛋白E
肝X受体
化学
细胞生物学
内分泌学
内科学
生物化学
医学
免疫学
转录因子
炎症
核受体
酶
疾病
运输机
基因
作者
Tao Wang,Yunxia Zhou,Yunping Fan,Hao Duan,Xiaoyu Guo,Jinlong Chang,Youheng Jiang,Changxue Li,Zhiqiang Fu,Yunfei Gao,Xiaoran Guo,Kastytis Šidlauskas,Zhenqiang He,Clive Da Costa,Xia Sheng,Dinglan Wu,Jinqiu Yuan,Hui‐Liang Li,Yulong He,Yonggao Mou,Ningning Li
标识
DOI:10.1002/advs.202205949
摘要
Isocitrate dehydrogenase (IDH) mutation, a known pathologic classifier, initiates metabolic reprogramming in glioma cells and has been linked to the reaction status of glioma-associated microglia/macrophages (GAMs). However, it remains unclear how IDH genotypes contribute to GAM phenotypes. Here, it is demonstrated that gliomas expressing mutant IDH determine M1-like polarization of GAMs, while archetypal IDH induces M2-like polarization. Intriguingly, IDH-mutant gliomas secrete excess cholesterol, resulting in cholesterol-rich, pro-inflammatory GAMs without altering their cholesterol biosynthesis, and simultaneously exhibiting low levels of tumoral cholesterol due to expression remodeling of cholesterol transport molecules, particularly upregulation of ABCA1 and downregulation of LDLR. Mechanistically, a miR-19a/LDLR axis-mediated novel post-transcriptional regulation of cholesterol uptake is identified, modulated by IDH mutation, and influencing tumor cell proliferation and invasion. IDH mutation-induced PERK activation enhances cholesterol export from glioma cells via the miR-19a/LDLR axis and ABCA1/APOE upregulation. Further, a synthetic PERK activator, CCT020312 is introduced, which markedly stimulates cholesterol efflux from IDH wild-type glioma cells, induces M1-like polarization of GAMs, and consequently suppresses glioma cell invasion. The findings reveal an essential role of the PERK/miR-19a/LDLR signaling pathway in orchestrating gliomal cholesterol transport and the subsequent phenotypes of GAMs, thereby highlighting a novel potential target pathway for glioma therapy.
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