PTBP2-Mediated Alternative Splicing of IRF9 Controls Tumor-Associated Monocyte/Macrophage Chemotaxis and Repolarization in Neuroblastoma Progression.
PTBP2-Mediated Alternative Splicing of IRF9 Controls Tumor-Associated Monocyte/Macrophage Chemotaxis and Repolarization in Neuroblastoma Progression.
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DOI：
10.34133/research.0033
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Miao L
中科院分区：
文献类型：
--
作者：
Tang J;He J;Guo H;Lin H;Li M;Yang T;Wang HY;Li D;Liu J;Li L;Xia H;Zhuo Z;Miao L
小儿纵隔神经母细胞瘤（NB）在手术、化疗或放疗后也会发生复发和转移。针对肿瘤微环境的策略已被报道可以提高生存率;然而，对NB中具有专门功能的单核细胞和肿瘤相关巨噬细胞（M β）的彻底调查仍然缺乏。我们的数据首次证明，多聚嘧啶道结合蛋白2（PTBP 2）作为一个可能的标识符与纵隔NB患者筛选的蛋白质组学分析和PTBP 2预测良好的结果。功能研究表明，NB细胞中的PTBP 2诱导肿瘤相关单核细胞和M β的趋化活性和复极化，这反过来又抑制NB的生长和传播。PTBP 2在机制上阻止干扰素调节因子9选择性剪接并上调信号转导子和转录激活子1以刺激C-C基序趋化因子配体5（CCL 5）和干扰素刺激的基因因子依赖性I型干扰素分泌，诱导单核细胞/巨噬细胞趋化性，并维持单核细胞的促炎表型。我们的研究确定了在NB进展中PTBP 2诱导的单核细胞/单核细胞的关键事件，并揭示了PTBP 2发生的RNA剪接有利于NB细胞和单核细胞之间的免疫区室化。这项工作揭示了PTBP 2在NB发展中的病理和生物学作用，并表明PTBP 2诱导的RNA剪接有利于免疫区室化，并预测纵隔NB的良好预后。
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.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
5.6
作者：
Korbecki J;Kojder K;Simińska D;Bohatyrewicz R;Gutowska I;Chlubek D;Baranowska-Bosiacka I
通讯作者：
Baranowska-Bosiacka I
DOI：
10.1038/nrm.2017.27
发表时间：
2017-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Baralle FE;Giudice J
通讯作者：
Giudice J
影响因子：
8
作者：
Huffman, Austin P.;Lin, Jeffrey H.;Vonderheide, Robert H.
通讯作者：
Vonderheide, Robert H.
影响因子：
64.8
作者：
Bertram, Karl;Agafonov, Dmitry E.;Luehrmann, Reinhard
通讯作者：
Luehrmann, Reinhard