中性粒细胞胞外陷阱
肿瘤微环境
免疫系统
炎症
先天免疫系统
转移
下调和上调
癌症研究
车站3
癌症
信号转导
医学
免疫学
细胞生物学
生物
内科学
生物化学
基因
作者
Zezhong Mou,Yiling Chen,Jinzhong Hu,Yun Hu,Lujia Zou,Xinan Chen,Shenghua Liu,Qiuping Yin,Jian Gong,Li Shu,Shanhua Mao,Chenyang Xu,Haowen Jiang
标识
DOI:10.1016/j.apsb.2024.06.029
摘要
Tumor relapse and metastasis are the major causes of mortality associated with urothelial cancer. In the tumor microenvironment, negative regulatory molecules and various immune cell subtypes suppress antitumor immunity. The inflammatory microenvironment, associated with neutrophils and neutrophil extracellular traps (NETs), promotes tumor metastasis. However, no drugs are currently available to specifically inhibit neutrophils and NETs. In this study, we first demonstrated that icaritin (ICT), a Chinese herbal remedy that is a first-line treatment for advanced and incurable hepatocellular carcinoma, reduces NETs caused by suicidal NETosis and prevents neutrophil infiltration in the tumor microenvironment. Mechanistically, ICT binds to and inhibits the expression of PADI2 in neutrophils, thereby suppressing PADI2-mediated histone citrullination. Moreover, ICT inhibits ROS generation, suppresses the MAPK signaling pathway, and inhibits NET-induced tumor metastasis. Simultaneously, ICT inhibits tumoral PADI2-mediated histone citrullination, which consequently suppresses the transcription of neutrophil-recruiting genes such as GM-CSF and IL-6. The downregulation of IL-6 expression, in turn, forms a regulatory feedback loop through the JAK2/STAT3/IL-6 axis. Through a retrospective study of clinical samples, we found a correlation between neutrophils, NETs, UCa prognosis, and immune evasion. Combining ICT with immune checkpoint inhibitors may have synergistic effects. In summary, our study demonstrated that ICT could be a novel inhibitor of NETs and a novel UCa treatment.
科研通智能强力驱动
Strongly Powered by AbleSci AI