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Project description:miR-196b-TLR7/8 signaling axis regulates innate immune signaling and myeloid maturation in DNMT3A-mutant AML
| PRJNA707593 | ENA
Project description:As a new type of non-coding RNA, the role of circular RNA (circRNA) in various diseases and tumors has received considerable attention. Studies have shown that circRNAs play an important role in the progression of acute myeloid leukemia (AML) via different mechanisms. However, the specific underlying molecular mechanism of circRNAs in the proliferation of AML cells remians unclear. This study aimed to clarify the biological role and mechanism of circCRKL in AML. The results indicated low circCRKL expression in AML cell lines and samples. Moreover, the overexpression of circCRKL inhibited the proliferation and colony-forming ability of AML cells, while its silencing promoted them. In addition, bioinformatics tools and luciferase assays revealed that circCRKL could sponge miR-196a-5p and miR-196b-5p to promote the expression of p27. Furthermore, circCRKL inhibited AML cell proliferation via the miR-196a-5p/miR-196b-5p/p27 axis, suggesting a potential new target for AML therapy.
| S-EPMC8806729 | biostudies-literature
Project description:Interferon (IFN)-γ is the major mediator of anti-tumor immune responses; nevertheless, cancer cells use intrigue strategies to alter IFN-γ signaling and avoid elimination. Understanding the immune regulatory mechanisms employed by acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells upon exposure to IFN-γ is critical for development of immunotherapy and checkpoint blockade therapy approaches. This study aims to explore the influence of myeloid maturation on IFN-γ-induced PD-L1 and PD-L2 expression and on pro-leukemogenic transcription factor STAT3 signaling in AML and MDS. Stimulation of myeloid blasts' maturation by all-trans retinoic acid (ATRA) or 1α,25-dihydroxyvitamin D3 (vitamin D) increased the CD11b+ fraction that expressed PD-1 ligands in response to IFN-γ. Intriguingly, STAT3 pathway was potently induced by IFN-γ and strengthened upon prolonged exposure. Nonetheless, STAT3-mediated atypical IFN-γ signaling appeared as a negligible factor for PD-L1 and PD-L2 expression. These negative influences of IFN-γ could be alleviated by a small-molecule inhibitor of STAT3, stattic, which also inhibited the upregulation of PD-L1. In conclusion, induction of myeloid maturation enhances the responsiveness of AML and MDS cells to IFN-γ. However, these malignant myeloid cells can exploit both STAT3 pathway and PD-1 ligands to survive IFN-γ-mediated immunity and maintain secondary immune resistance.
| S-EPMC6691003 | biostudies-literature
Project description:Differential expression of microRNAs (miRNAs) has been implicated in leukemogenesis. We investigate the expression pattern of miR-196b. Using quantitative real-time PCR (qRT-PCR), we detected the expression of miR-196b and its correlated genes (SMC1A/MLH1) in initial pediatric AML. A significant association was observed between overexpression of miR-196b and inferior overall survival of pediatric AML (Log Rank P<0.0001). AML M4/5 subtype, high white blood cell (WBC) count at presentation, MLL rearrangement, or FLT3-ITD mutation at diagnosis and non-remission group after the first induction chemotherapy possessed higher miR-196b expression. Furthermore, a positive relationship was found between the expression of miR-196b and SMC1A/MLH1 (Spearman's r=0.37 and 0.44, P=0.001 and <0.0001, respectively). Taken together, these findings suggest that differentially high expression of miR-196b in diagnostic marrow samples of pediatric AML is associated with unfavorable outcome, and miR-196b potentially can be a novel biomarker for the diagnosis, prognosis and treatment in pediatric AML.
| S-EPMC5427473 | biostudies-literature
Project description:The zinc finger protein growth factor independent-1 (Gfi1) is a transcriptional repressor that is critically required for normal granulocytic differentiation. GFI1 loss-of-function mutations are found in some patients with severe congenital neutropenia (SCN). The SCN-associated GFI1-mutant proteins act as dominant negatives to block granulopoiesis through selective deregulation of a subset of GFI1 target genes. Here we show that Gfi1 is a master regulator of microRNAs, and that deregulated expression of these microRNAs recapitulates a Gfi1 loss-of-function block to granulocyte colony-stimulating factor (G-CSF)-stimulated granulopoiesis. Specifically, bone marrow cells from a GFI1-mutant SCN patient and Gfi1(-/-) mice display deregulated expression of miR-21 and miR-196B expression. Flow cytometric analysis and colony assays reveal that the overexpression or depletion of either miR induces changes in myeloid development. However, coexpression of miR-21 and miR-196b (as seen in Gfi1(-/-) mice and a GFI1N382S SCN patient) completely blocks G-CSF-induced granulopoiesis. Thus, our results not only identify microRNAs whose regulation is required during myelopoiesis, but also provide an example of synergy in microRNA biologic activity and illustrate potential mechanisms underlying SCN disease pathogenesis.
| S-EPMC2680372 | biostudies-literature
Project description:MicroRNAs (miRNAs) can function as tumor suppressors or oncogene promoters during tumor development. In this study, low levels of expression of miR-196b were detected in patients with chronic myeloid leukemia. Bisulfite genomic sequencing PCR and methylation-specific PCR were used to examine the methylation status of the CpG islands in the miR-196b promoter in K562 cells, patients with leukemia and healthy individuals. The CpG islands showed more methylation in patients with chronic myeloid leukemia compared with healthy individuals (P<0.05), which indicated that low expression of miR-196b may be associated with an increase in the methylation of CpG islands. The dual-luciferase reporter assay system demonstrated that BCR-ABL1 and HOXA9 are the target genes of miR-196b, which was consistent with predictions from bioinformatics software analyses. Further examination of cell function indicated that miR-196b acts to reduce BCR-ABL1 and HOXA9 protein levels, decrease cell proliferation rate and retard the cell cycle. A low level of expression of miR-196b can cause up-regulation of BCR-ABL1 and HOXA9 expression, which leads to the development of chronic myeloid leukemia. MiR-196b may represent an effective target for chronic myeloid leukemia therapy.
| S-EPMC3716876 | biostudies-literature
Project description:Our recent study demonstrated that the QKI-5 regulated miRNA, miR-196b-5p, and it functions as an onco-microRNA in non-small cell lung cancer (NSCLC) by directly targeting GATA6 and TSPAN12. However, the role of miR-196b-5p in NSCLC progression and metastasis still remains unclear. We found that miR-196b-5p promotes lung cancer cell proliferation and colony formation by directly targeting tumor suppressor, FAS. The expression of FAS was significantly downregulated in NSCLC tissue samples and was negatively correlated with the miR-196b-5p expression. Knocking down FAS activates NFkB signaling and subsequent IL6 secretion, resulting in phosphorylation of signal transducer and activator of transcription 3 (STAT3) to promote lung cancer cell growth. Our findings indicated that miR-196b-5p might exhibit novel oncogenic function by FAS-mediated STAT3 activation in NSCLC, and suggested that targeting the miR-196b-5p/FAS/NFkB/IL6/STAT3 pathway might be a promising therapeutic strategy in treating NSCLC.
| S-EPMC7508872 | biostudies-literature
Project description:UDP-glucuronosyltransferase (UGT) 2A1 is an important enzyme in the detoxification of polycyclic aromatic hydrocarbons found in cigarette smoke. This enzyme is expressed in aerodigestive tract tissues including lung as both its wild-type and exon 4-deleted splice variant isoforms, with the latter acting as a negative regulator of wild-type UGT2A1 activity. UGT2A1 regulation may also be mediated by microRNA (miRNA). To identify miRNA important in the regulation of UGT2A1, expression analysis in tandem with in silico analysis suggested miR-196a-5p and miR-196b-5p as potential top candidates. Significant reductions in firefly luciferase activity were observed in human embryonic kidney cell line 293 cells cotransfected with the wild-type UGT2A1 3'-untranslated region (UTR)-containing luciferase plasmid and either miR-196a-5p (62%, P = 0.00080) or miR-196b-5p (60%, P = 0.00030) mimics. In pull-down assays, there was a 3.4- and 5.2-fold increase in miR-196a-5p (P = 0.054) and miR-196b-5p (P = 0.035), respectively, using the UGT2A1 3'-UTR biotinylated mRNA probe as compared with the ?-actin coding region control mRNA probe. UGT2A1 mRNA was reduced by 25% (P = 0.058) and 35% (P = 0.023) in H146 and H1944 cells, respectively, after overexpression of the miR196a-5p mimic. A similar 32% (P = 0.030) and 41% (P = 0.016) reduction was observed after over-expression of the miR-196b-5p mimic. In H146 cells transfected with miRNA mimic together with a small interfering RNA (siRNA) specific for the UGT2A1 splice variant, a significant reduction in 3-hydroxy-benzo[a]pyrene-glucuronide formation was observed. The miR-196a-5p- and miR-196b-55p-treated cells exhibited reductions of 35% (P = 0.047) and 44% (P = 0.0063), respectively. These data suggest that miR-196a-5p and miR-196b-5p play an important role in UGT2A1 regulation within the lung and potentially other aerodigestive tract tissues.
| S-EPMC6439457 | biostudies-literature
Project description:Osteoarthritis (OA) is the most prevalent joint disorder associated with severe chronic pain. Although synovial inflammation is well correlated with pain severity, the molecular mechanism responsible for OA pain remains unclear. Here, we show that extracellular miR-21 released from synovial tissue mediates knee OA pain in surgical OA model rats. miR-21 was the most abundant among increased microRNAs (miRNAs) in the synovial tissue. miR-21 was released into extracellular space from the synovial tissue and increased in the synovial fluid. A single intra-articular injection of miR-21 inhibitor exerted long-term analgesia of knee OA pain, whereas miR-21 injection in naive rats caused knee joint pain. miR-21 mutant, which lacks the Toll-like receptor (TLR) binding motif, but not in the seed sequence, did not cause joint pain, suggesting a non-canonical mode of action different from translational repression. Consistent with this, the algesic effect of miR-21 was blocked by antagonizing TLR7. The TLR7 antagonist also exerted a long-lasting analgesic effect on knee OA pain. Therefore, extracellular miR-21 released from synovial tissue mediates knee OA pain through TLR7 activation in surgical OA model rats. Extracellular miRNA in the joint may be a plausible target for pain therapy, providing a novel analgesic strategy for OA.
| S-EPMC6920297 | biostudies-literature
Project description:The use of human mesenchymal stem cells (hMSCs) in clinical applications requires large-scale cell expansion prior to administration. However, the prolonged culture of hMSCs results in cellular senescence, impairing their proliferation and therapeutic potentials. To understand the role of microRNAs (miRNAs) in regulating cellular senescence in hMSCs, we globally depleted miRNAs by silencing the DiGeorge syndrome critical region 8 (DGCR8) gene, an essential component of miRNA biogenesis. DGCR8 knockdown hMSCs exhibited severe proliferation defects and senescence-associated alterations, including increased levels of reactive oxygen species (ROS). Transcriptomic analysis revealed that the antioxidant gene superoxide dismutase 2 (SOD2) was significantly downregulated in DGCR8 knockdown hMSCs. Moreover, we found that DGCR8 silencing in hMSCs resulted in hypermethylation in CpG islands upstream of SOD2. 5-aza-2'-deoxycytidine treatment restored SOD2 expression and ROS levels. We also found that these effects were dependent on the epigenetic regulator DNA methyltransferase 3 alpha (DNMT3A). Using computational and experimental approaches, we demonstrated that DNMT3A expression was regulated by miR-29a-3p and miR-30c-5p. Overexpression of miR-29a-3p and/or miR-30c-5p reduced ROS levels in DGCR8 knockdown hMSCs and rescued proliferation defects, mitochondrial dysfunction, and premature senescence. Our findings provide novel insights into hMSCs senescence regulation by the miR-29a-3p/miR-30c-5p/DNMT3A/SOD2 axis.
| S-EPMC7509080 | biostudies-literature