MiR-146a-5p deficiency in extracellular vesicles of glioma-associated macrophages promotes epithelial-mesenchymal transition through the NF-?B signaling pathway

作者全名："Xu, Chao; Wang, Pan; Guo, Haiyan; Shao, Chuan; Liao, Bin; Gong, Sheng; Zhou, Yanghao; Yang, Bingjie; Jiang, Haotian; Zhang, Gang; Wu, Nan"

作者地址："[Xu, Chao; Wang, Pan; Shao, Chuan; Liao, Bin; Jiang, Haotian; Zhang, Gang; Wu, Nan] Chongqing Med Univ, Chongqing, Peoples R China; [Xu, Chao; Wang, Pan; Shao, Chuan; Jiang, Haotian; Zhang, Gang; Wu, Nan] Chinese Acad Sci, Chongqing Inst Green & Intelligent Technol, Chongqing, Peoples R China; [Xu, Chao; Wang, Pan; Shao, Chuan; Jiang, Haotian; Zhang, Gang; Wu, Nan] Univ Chinese Acad Sci, Chongqing Sch, Chongqing, Peoples R China; [Xu, Chao; Wang, Pan; Guo, Haiyan; Shao, Chuan; Liao, Bin; Gong, Sheng; Zhou, Yanghao; Yang, Bingjie; Jiang, Haotian; Zhang, Gang; Wu, Nan] Chongqing Gen Hosp, Dept Neurosurg, Chongqing, Peoples R China; [Guo, Haiyan; Yang, Bingjie] Univ Chinese Acad Sci, Coll Life Sci, Beijing, Peoples R China"

通信作者："Wu, N (通讯作者)，Chongqing Med Univ, Chongqing, Peoples R China.; Wu, N (通讯作者)，Chinese Acad Sci, Chongqing Inst Green & Intelligent Technol, Chongqing, Peoples R China.; Wu, N (通讯作者)，Univ Chinese Acad Sci, Chongqing Sch, Chongqing, Peoples R China.; Wu, N (通讯作者)，Chongqing Gen Hosp, Dept Neurosurg, Chongqing, Peoples R China."

来源：CELL DEATH DISCOVERY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001022405100005

JCR分区：Q1

影响因子：6.1

年份：2023

卷号：9

期号：1

开始页：　

结束页：　

文献类型：Article

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摘要："Glioma-associated macrophages (GAMs) are pivotal chains in the tumor immune microenvironment (TIME). GAMs mostly display M2-like phenotypes with anti-inflammatory features related to the malignancy and progression of cancers. Extracellular vesicles derived from immunosuppressive GAMs (M2-EVs), the essential components of the TIME, greatly impact the malignant behavior of GBM cells. M1- or M2-EVs were isolated in vitro, and human GBM cell invasion and migration were reinforced under M2-EV treatment. Signatures of the epithelial-mesenchymal transition (EMT) were also enhanced by M2-EVs. Compared with M1-EVs, miR-146a-5p, considered the key factor in TIME regulation, was deficient in M2-EVs according to miRNA-sequencing. When the miR-146a-5p mimic was added, EMT signatures and the invasive and migratory abilities of GBM cells were correspondingly weakened. Public databases predicted the miRNA binding targets and interleukin 1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) were screened as miR-146a-5p binding genes. Bimolecular fluorescent complementation and coimmunoprecipitation confirmed interactions between TRAF6 and IRAK1. The correlation between TRAF6 and IRAK1 was evaluated with immunofluorescence (IF)-stained clinical glioma samples. The TRAF6-IRAK1 complex is the switch and the brake that modulates IKK complex phosphorylation and NF-?B pathway activation, as well as the EMT behaviors of GBM cells. Furthermore, a homograft nude mouse model was explored and mice transplanted with TRAF6/IRAK1-overexpressing glioma cells had shorter survival times while mice transplanted with glioma cells with miR-146a-5p overexpression or TRAF6/IRAK1 knockdown lived longer. This work indicated that in the TIME of GBM, the deficiency of miR-146a-5p in M2-EVs enhances tumor EMT through disinhibition of the TRAF6-IRAK1 complex and IKK-dependent NF-?B signaling pathway providing a novel therapeutic strategy targeting the TIME of GBM."

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