Mouse 4T1 Breast Cancer Cell-Derived Exosomes Induce Proinflammatory Cytokine Production in Macrophages via miR-183
Mouse 4T1 Breast Cancer Cell-Derived Exosomes Induce Proinflammatory Cytokine Production in Macrophages via miR-183
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小鼠4T1乳腺癌细胞来源的外泌体通过miR-183诱导巨噬细胞产生促炎细胞因子
DOI：
10.4049/jimmunol.1901104
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发表时间：
2020-11-15
影响因子：
4.4
通讯作者：
Luo, Yunping
中科院分区：
文献类型：
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作者：
Guo, Jian;Duan, Zhaojun;Luo, Yunping
肿瘤相关巨噬细胞（tumor -associated macrophages， TAMS）在肿瘤炎症微环境中起关键作用，促进肿瘤生长和转移。大多数类型的肿瘤异常表达microRNAs (miRNAs)，其可以通过外泌体在细胞间转移，并调节受体细胞中的基因表达，但肿瘤来源的miRNAs是否通过外泌体转移并调节TAM表型尚不清楚。我们报道了小鼠4T1乳腺癌细胞源性外泌体增强了TAM中IL-1 β、IL-6和tnf - α的表达，并且在4T1乳腺癌模型中，通过短发卡RNA介导的Rab27a/b缺失抑制4T1细胞外泌体分泌可抑制肿瘤生长和转移，并显著下调IL-1 β、IL-6和tnf - α。此外，miRNA表达谱显示，三种miRNA （miR-100-5p， miR-183-5p和miR-125b-1-3p）在4T1细胞外泌体中的含量明显高于小鼠骨髓源性巨噬细胞，这表明miRNA可能通过外泌体介导转移，值得注意的是，miR-183-5p被发现通过外泌体从4T1细胞转移到巨噬细胞。此外，PPP2CA被证实是miR-183-5p的靶基因，PPP2CA下调可增强NF-kappa B信号传导，促进巨噬细胞IL-1 β、IL-6和tnf - α的表达。最后，当在4T1细胞中通过miR-183-5p海绵表达下调外泌体中的miR-183-5p时，这些4T1来源的外泌体引发p65磷酸化和IL-1 β、IL-6和tnf - α分泌减少，miRNA下调也导致体内4T1乳腺肿瘤模型中肿瘤生长和转移受到抑制。因此，在乳腺癌模型中，肿瘤细胞中表达的miR-183-5p通过外泌体转移到巨噬细胞中，通过抑制PPP2CA的表达促进促炎细胞因子的分泌，从而促进肿瘤的进展。
Tumor-associated macrophages (TAMS) play a critical role in the tumor inflammatory microenvironment and facilitate tumor growth and metastasis. Most types of tumors aberrantly express microRNAs (miRNAs), which can be transferred between cells by exosomes and can regulate gene expression in recipient cells, but it remains unclear whether tumor-derived miRNAs are transferred by exosomes and regulate the TAM phenotype. We report that mouse 4T1 breast cancer cell-derived exosomes enhanced TAM expression of IL-1 beta, IL-6, and TNF-alpha and that inhibition of 4T1-cell exosome secretion through short hairpin RNA- mediated Rab27a/b depletion repressed tumor growth and metastasis and markedly downregulated IL-1 beta, IL-6, and TNF-alpha in a 4T1 breast tumor model. Furthermore, miRNA expression profiling revealed that three miRNAs (miR-100-5p, miR-183-5p, and miR-125b-1-3p) were considerably more abundant in 4T1 cell exosomes than in mouse bone marrow-derived macrophages, indicating potential exosome-mediated transfer of the miRNAs, and, notably, miR-183-5p was found to be transferred from 4T1 cells to macrophages through exosomes. Moreover, PPP2CA was verified as an miR-183-5p target gene, and PPP2CA downregulation enhanced NF-kappa B signaling and promoted macrophage expression of IL-1 beta, IL-6, and TNF-alpha. Lastly, when miR-183-5p was downregulated in exosomes through miR-183-5p sponge expression in 4T1 cells, these 4T1-derived exosomes triggered diminished p65 phosphorylation and IL-1 beta, IL-6, and TNF-alpha secretion, and the miRNA downregulation also led to repression of tumor growth and metastasis in the 4T1 breast tumor model in vivo. Thus, miR-183-5p expressed in tumor cells was transferred to macrophages by exosomes and promoted the secretion of proinflammatory cytokines by inhibiting PPP2CA expression, which contributed to tumor progression in a breast cancer model.