期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 120, 期 4, 页码 5936-5948出版社
WILEY
DOI: 10.1002/jcb.27882
关键词
interleukin-17A (IL-17A); migration and invasion; miR-146b-5p; nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B); T-cell acute lymphoblastic leukemia (T-ALL)
资金
- National Natural Science Foundation of China [81501352, 81541027, 81500151, 81270607, 81770180, 81400121]
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.
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