Loss of miR-146b-5p promotes T cell acute lymphoblastic leukemia migration and invasion via the IL-17A pathway
Loss of miR-146b-5p promotes T cell acute lymphoblastic leukemia migration and invasion via the IL-17A pathway
复制标题
miR-146b-5p的缺失通过IL-17A途径促进T细胞急性淋巴细胞白血病迁移和侵袭
DOI：
10.1002/jcb.27882
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发表时间：
2019-04-01
影响因子：
4
通讯作者：
Zhang, Qiuping
中科院分区：
文献类型：
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作者：
Tu, Zhenbo;Xiong, Jie;Zhang, Qiuping
转移性疾病仍然是T细胞急性淋巴细胞白血病（T- all）患者死亡的主要原因。microRNAs （miRNAs）通过在转录后水平抑制基因表达，在T-ALL的发病机制中发挥重要作用。当前项目的目标是鉴定T-ALL转移中任何重要的mirna。我们观察到miR-146b-5p在T-ALL患者和细胞系中下调，生物信息学分析表明miR-146b-5p与造血系统有关。miR-146b-5p抑制T-ALL细胞的迁移和侵袭。白细胞介素- 17a （IL-17A）被预测为miR-146b-5p的靶标；荧光素酶测定证实了这一点。有趣的是，T-ALL患者和细胞系分泌IL-17A并表达IL-17A受体（IL-17RA）。IL-17A/IL-17RA相互作用促进T-ALL细胞的迁移和侵袭反应。基因集富集分析（GSEA）和定量聚合酶链反应（qPCR）分析表明，基质金属肽酶-9 （MMP9）是IL-17A活化的潜在下游效应因子，活化B细胞的核因子kappa-轻链增强子（NF-kappa B）信号也参与了这一过程。此外，在IL-17A（-/-）小鼠模型中，IL-17A激活促进T-ALL细胞向肝脏转移。这些结果表明，T-ALL中miR-146b-5p表达的降低可能导致IL-17A的上调，IL-17A通过NF-kappa B信号通路上调MMP9，从而促进T-ALL细胞迁移和侵袭。
Metastatic disease remains the primary cause of death for individuals with T cell acute lymphoblastic leukemia (T-ALL). microRNAs (miRNAs) play important roles in the pathogenesis of T-ALL by inhibiting gene expression at posttranscriptional levels. The goal of the current project is to identify any significant miRNAs in T-ALL metastasis. We observed miR-146b-5p to be downregulated in T-ALL patients and cell lines, and bioinformatics analysis implicated miR-146b-5p in the hematopoietic system. miR-146b-5p inhibited the migration and invasion in T-ALL cells. Interleukin-17A (IL-17A) was predicted to be a target of miR-146b-5p; this was confirmed by luciferase assays. Interestingly, T-ALL patients and cell lines secreted IL-17A and expressed the IL-17A receptor (IL-17RA). IL-17A/IL-17RA interactions promoted strong T-ALL cell migration and invasion responses. Gene set enrichment analysis (GSEA) and quantitative polymerase chain reaction (qPCR) analysis indicated that matrix metallopeptidase-9 (MMP9), was a potential downstream effector of IL-17A activation, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling was also implicated in this process. Moreover, IL-17A activation promoted T-ALL cell metastasis to the liver in IL17A(-/-) mouse models. These results indicate that reduced miR-146b-5p expression in T-ALL may lead to the upregulation of IL-17A, which then promotes T-ALL cell migration and invasion by upregulating MMP9 via NF-kappa B signaling.