Icaritin inhibits the progression of urothelial cancer by suppressing PADI2-mediated neutrophil infiltration and neutrophil extracellular trap formation  

作　　者：Zezhong Mou Yiling Chen Jinzhong Hu Yun Hu Lujia Zou Xinan Chen Shenghua Liu Qiuping Yin Jian Gong Shuchen Li Shanhua Mao Chenyang Xu Haowen Jiang 

机构地区：[1]Department of Urology,Huashan Hospital,Fudan University,Shanghai 200040,China [2]Fudan Institute of Urology,Fudan University,Shanghai 200040,China [3]National Clinical Research Center for Aging and Medicine,Fudan University,Shanghai 200040,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第9期3916-3930,共15页药学学报（英文版）

基　　金：grants from National Natural Science Foundation of China(No.82373222,No.82202970);Leading Talent Program by Shanghai Municipal Health Commission(2022LJ008,China);Shanghai Shenkang Hospital Development Center(SHDC12021104,China);Science and Technology Commission of Shanghai Municipality(22Y21900200&22YF1404300,China).

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.

关 键 词：ICARITIN NEUTROPHIL Neutrophil extracellular trap PADI2 Urothelial cancer 

分 类 号：R737.13[医药卫生—肿瘤]