Loss of miR‐146b‐5p promotes T cell acute lymphoblastic leukemia migration and invasion via the IL‐17A pathway

Abstract

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‐κB) 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‐κB signaling.

DNA methylation‐mediated silencing of microRNA‐204 enhances T cell acute lymphoblastic leukemia by up‐regulating MMP‐2 and MMP‐9 via NF‐κB

“…32 Similarly, Tu et al found that loss of miR-146b-5p up-regulated MMP-9 expression via the NF-κB signalling pathway, to promote T-ALL cell migration and invasion. 6 Very importantly, previous evidence also highlighted that IRAK-1 could lead to the activation of NF-κB. 33 In conclusion, our study elucidated the possible pathway that DNA methylation at the promotor region causes miR-204 silencing,…”

“…inhibitor-NC, (4) inhibitor-miR-204, (5) mimic-NC + oe-NC, (6) mimic-miR-204 + oe-NC, (7) mimic-miR-204 + oe-IRAK1, (8) mimic-NC + oe-NC, (9) mimic-miR-204 + oe-NC, (10) mimic-miR-204 + oe-p65, (11) oe-NC + si-NC, (12) oe-IRAK1 + si-NC or (13) oe-IRAK1 + si-p65.…”

The role of microRNAs in acute lymphoblastic leukaemia: From biology to applications

“…Downregulation of miR‐146b in T cell ALL has been reported. A study by Tu et al demonstrated that loss of miR‐146b contributes to the promotion of metastasis through the IL7A pathway. Mechanistically, MMP‐9 is a potential effector of IL7A, and IL7A is a target gene for miR‐146b.…”

“…Mechanistically, MMP‐9 is a potential effector of IL7A, and IL7A is a target gene for miR‐146b. Therefore, miR‐146b acts as a tumour suppressor miRNA in T cell ALL, and downregulation of miR‐146b is associated with poor prognosis and the promotion of metastasis in T cell ALL …”

miR‑146b correlates with increased disease activity and psoriatic tissue inflammation and promotes keratinocyte proliferation in psoriasis

“…Accumulating studies have revealed that miRNAs are widely distributed in animals, plants and certain viruses, and they have been determined to be key regulators of numerous important biological processes, including cell proliferation, differentiation and inflammation (9)(10)(11). As one of the commonly investigated miRNAs, miR-146b has been implicated in the malignant proliferation of various cancer cell types (including ovarian and papillary thyroid cancer cells) and several immune activities, including innate immune sensing and pro-inflammatory cytokine release (12)(13)(14)(15)(16). Several studies have revealed that miR-146b expression is increased in several autoimmune diseases [including rheumatoid arthritis (RA), multiple sclerosis and autoimmune thyroid diseases (ATD)] (17)(18)(19).…”