PTBP2-Mediated Alternative Splicing of IRF9 Controls Tumor-Associated Monocyte/Macrophage Chemotaxis and Repolarization in Neuroblastoma Progression  

作　　者：Jue Tang Jing He Huiqin Guo Huiran Lin Meng Li Tianyou Yang Hai-Yun Wang Di Li Jiabin Liu Le Li Huimin Xia Zhenjian Zhuo Lei Miao 

机构地区：[1]Department of Pediatric Surgery,Guangzhou Institute of Pediatrics,Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease,Guangzhou Women and Children’s Medical Center,Guangzhou Medical University,Guangzhou 510623,Guangdong,China [2]School of Medicine,South China University of Technology,Guangzhou,Guangdong 510623,China [3]Faculty of Medicine,Macao University of Science and Technology,Macao 999078,China [4]Laboratory Animal Center,School of Chemical Biology and Biotechnology,Peking University Shenzhen Graduate School,Shenzhen 518055,China

出　　处：《Research》2023年第3期547-563,共17页研究（英文）

基　　金：from National Natural Science Foundation of China(82002635,82002636,and 82173593);Guangzhou Science and Technology Project(202102021227 and 202102020421);Shenzhen Municipal Commission of Science and Technology Innovation(JCYJ20220531093213030)。

摘　　要：The recurrence and metastasis of children with mediastinal neuroblastoma(NB)are also occurred after surgery,chemotherapy,or radiotherapy.Strategies targeting the tumor microenvironment have been reported to improve survival;however,thorough investigations of monocytes and tumor-associated macrophages(Mϕs)with specialized functions in NB are still lacking.Our data first demonstrated polypyrimidine tract binding protein 2(PTBP2)as a possible identifier in patients with mediastinal NB screened by proteomic profiling and that PTBP2 predicted good outcomes.Functional studies revealed that PTBP2 in NB cells induced the chemotactic activity and repolarization of tumor-associated monocytes and Mϕs,which,in turn,inhibited NB growth and dissemination.Mechanistically,PTBP2 prevents interferon regulatory factor 9 alternative splicing and upregulates signal transducers and activators of transcription 1 to stimulate C-C motif chemokine ligand 5(CCL5)and interferon-stimulated gene factor-dependent type I interferon secretion,to induce monocyte/Mϕs chemotaxis,and to sustain monocytes in a proinflammatory phenotype.Our study defined a critical event of PTBP2-induced monocytes/Mϕs in NB progression and revealed that RNA splicing occurred by PTBP2 benefits immune compartmentalization between NB cells and monocytes.This work revealed the pathological and biological role of PTBP2 in NB development and indicates that PTBP2-induced RNA splicing benefits immune compartmentalization and predicted a favorable prognosis in mediastinal NB.

关 键 词：interferon inhibited specialized 

分 类 号：R73[医药卫生—肿瘤]