车站3
STAT蛋白
癌症研究
肿瘤微环境
信号转导
转录因子
肿瘤坏死因子α
巨噬细胞激活因子
生物
癌变
细胞生物学
化学
免疫学
癌症
免疫系统
生物化学
基因
淋巴因子
遗传学
肿瘤细胞
作者
Xiu-Ming Li,Yun Yang,Fuquan Jiang,Guang Hu,Shan Wan,Wenying Yan,Xiaoshun He,Fei Xiao,Xuemei Yang,Xingyi Guo,Jun Lü,Xiaoqin Yang,Junjie Chen,Wen-Long Ye,Yue Liu,Kaitlyn He,Hua Duan,Yu-Jia Zhou,Wen-Juan Gan,Feng Liu,Hua Wu
出处
期刊:Cell Reports
[Elsevier]
日期:2024-02-01
卷期号:43 (2): 113688-113688
被引量:1
标识
DOI:10.1016/j.celrep.2024.113688
摘要
Summary
Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.
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