MiRNA-142-3P and FUS can be Sponged by Long Noncoding RNA DUBR to Promote Cell Proliferation in Acute Myeloid Leukemia
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ABSTRACT:
SUBMITTER: Yin Z
PROVIDER: S-EPMC8570042 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Circular RNAs (circRNAs) could sponge micro-RNAs (miRNAs) to regulate tumor progression of hepatocellular carcinoma (HCC). Hsa_circ_104566 contributes to papillary thyroid carcinoma progression. However, the tumorigenic mechanism of hsa_circ_104566 on HCC remains enigmatic. The role of hsa_circ_104566 on HCC was therefore evaluated in this study. First, the high expression of hsa_circ_104566 was found in HCC tissues, which was significantly associated with poor prognosis in HCC patients. Second, Hsa_circ_104566 promoted HCC progression by decreasing apoptosis and E-cadherin, while increasing cell viability, proliferation, migration, invasion, and N-cadherin. On the other hand, HCC progression was suppressed by knockdown of hsa_circ_104566. Hsa_circ_104566 could target miR-338-3p, and its expression was negatively correlated with miR-338-3p in HCC patients. Moreover, miR-338-3p suppressed protein expression of Forkhead box protein 1 (FOXP1) and had a negative correlation with FOXP1 in HCC patients. Functional assay further indicated that the promotion of HCC progression by hsa_circ_104566 was reversed by miR-338-3p, and miR-338-3p inhibitor could counteract the effect of hsa_circ_104566 knockdown on the suppression of HCC progression. In vivo assay indicated that hsa_circ_104566 knockdown suppressed HCC tumor growth and metastasis. In conclusion, hsa_circ_104566 sponged miR-338-3p to promote HCC progression, providing a potential therapeutic target for cancer intervention.
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Project description:ObjectivesMicroRNAs (miRNAs) contribute to control of cell cycle progression and are frequently deregulated in cancer. The focus of this study was to determine effects of miR-142-3p on the cell cycle progression and cancer cell proliferation.Materials and methodsRT-qPCR was performed to determine expression of miR-142-3p in a range of cancer cell lines and in clinical cancer specimens. To further understand its role, we restored its expression in cancer cell lines by transfection with miR-142-3p mimics or inhibitors. Effects of miR-142-3p on cell cycle progression and cell proliferation were also determined.ResultsmiR-142-3p was down-regulated in both cancer cell lines and cancer specimens. Its overexpression suppressed proliferation, whereas its depletion promoted it. In addition, miR-142-3p lead to cell cycle arrest in G2/M. Moreover, CDC25C was identified as being a target of miR-142-3p, ectopic expression of which reversed suppression of cell proliferation.ConclusionsOur observations suggest that miR-142-3p functioned as a tumor suppressor by targeting CDC25C.
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Project description:The regulation of the balance between proliferation and differentiation in the mesenchymal compartment of the lung is largely uncharacterized, unlike its epithelial counterpart. In this study, we determined that miR-142-3p contributes to the proper proliferation of mesenchymal progenitors by controlling the level of WNT signaling. miR-142-3p can physically bind to adenomatous polyposis coli mRNA, functioning to regulate its expression level. In miR-142-3p loss-of-function experiments, proliferation of parabronchial smooth muscle cell progenitors is significantly impaired, leading to premature differentiation. Activation of WNT signaling in the mesenchyme, or Apc loss of function, can both rescue miR-142-3p knockdown. These findings show that in the embryonic lung mesenchyme, the microRNA machinery modulates the level of WNT signaling, adding an extra layer of control in the feedback loop between FGFR2C and ?-catenin-mediated WNT signaling.
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Project description:Recent evidence suggests that the ion channel TRPA1 is implicated in lung adenocarcinoma (LUAD), where its role and mechanism of action remain unknown. We have previously established that the membrane receptor FGFR2 drives LUAD progression through aberrant protein-protein interactions mediated via its C-terminal proline-rich motif. Here we report that the N-terminal ankyrin repeats of TRPA1 directly bind to the C-terminal proline-rich motif of FGFR2 inducing the constitutive activation of the receptor, thereby prompting LUAD progression and metastasis. Furthermore, we show that upon metastasis to the brain, TRPA1 gets depleted, an effect triggered by the transfer of TRPA1-targeting exosomal microRNA (miRNA-142-3p) from brain astrocytes to cancer cells. This downregulation, in turn, inhibits TRPA1-mediated activation of FGFR2, hindering the metastatic process. Our study reveals a direct binding event and characterizes the role of TRPA1 ankyrin repeats in regulating FGFR2-driven oncogenic process; a mechanism that is hindered by miRNA-142-3p.TRPA1 has been reported to contribute lung cancer adenocarcinoma (LUAD), but the mechanisms are unclear. Here the authors propose that TRPA1/FGFR2 interaction is functional in LUAD and show that astrocytes oppose brain metastasis by mediating the downregulation of TRPA1 through exosome-delivered miRNA-142-3p.
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Project description:Long noncoding RNAs (lncRNAs) have emerged as a class of pivotal regulators of gene expression. Recent studies have shown that lncRNAs contribute to the initiation, maintenance, and development of acute myeloid leukemia (AML). In this review, we summarize the current knowledge of the lncRNAs that play critical roles in AML. We first briefly describe the characteristics of lncRNAs, and then focus on their regulatory roles in AML, including the modulation of differentiation, proliferation, cell cycle, and apoptosis. We further emphasize the action of lncRNAs during leukemogenesis by describing how they interact with RNA, protein and chromatin DNA to exert their functions. We also highlight an urgent need to investigate the mechanisms by which lncRNAs contribute to the pathogenesis of AML. Finally, we discuss the prognostic value of lncRNAs in AML patients.
| S-EPMC5153810 | biostudies-other
Project description:Micro-RNAs (miRNAs) are small noncoding RNAs that regulate various biological pathways. As their role in phagocytosis remains poorly understood, we investigated their impact on phagocytosis in myeloid inflammatory cells. Seven miRNAs (miR-24, -30b, -101, 142-3p, -652-3p, -652-5p, and -1275) that were differentially expressed during monocyte to macrophage (M?) and monocyte to dendritic cell (DC) differentiation were screened for their potential role in phagocytosis. Among these, overexpression of miR-24, miR-30b, and miR-142-3p in human monocyte-derived M?, DC, monocytes, and PBMCs significantly attenuate phagocytosis of Escherichia coli and Staphylococcus aureus, as well as the secretion of inflammatory mediators, including TNF-?, IL-6, and IL-12p40. miRNA-mediated changes in cytokine profiles were observed at transcriptional and/or posttranscriptional levels and importantly exhibit miRNA-specific impact. To examine the underlying mechanism, we monitored the expression of phagocytosis pathway-associated genes and identified several genes that were altered in M? and DC transfected with miR-24, miR-30b, and miR-142-3p mimics. Some of these genes with altered expression also harbor putative miRNA binding sites. We show that miR-142-3p directly regulates protein kinase C? (PKC?), a key gene involved in phagocytosis. Interestingly, miR-142-3p and PKC? exhibit antagonistic expression during M? and DC differentiation. Short interfering RNA-mediated knockdown of PKC? in M? leads to reduced bacterial uptake, further highlighting the role of the gene in phagocytosis. Overall, these results demonstrate that miR-24, miR-30b, and miR-142-3p regulate phagocytosis and associated cytokine production in myeloid inflammatory cells through modulation of various genes involved in the pathway.
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Project description:BackgroundRunt-related transcription factor 1 (RUNX1) is one of the most frequently mutated genes in most of hematological malignancies, especially in acute myeloid leukemia. In the present study, we aimed to identify the key genes and microRNAs based on acute myeloid leukemia with RUNX1 mutation. The newly finding targeted genes and microRNA associated with RUNX1 may benefit to the clinical treatment in acute myeloid leukemia.Material/methodsThe gene and miRNA expression data sets relating to RUNX1 mutation and wild-type adult acute myeloid leukemia (AML) patients were downloaded from The Cancer Genome Atlas database. Differentially expressed miRNAs and differentially expressed genes (DEGs) were identified by edgeR of R platform. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed by Metascape and Gene set enrichment analysis. The protein-protein interaction network and miRNA-mRNA regulatory network were performed by Search Tool for the Retrieval of Interacting Genes database and Cytoscape software.ResultsA total of 27 differentially expressed miRNAs (25 upregulated and 2 downregulated) and 561 DEGs (429 upregulated and 132 downregulated) were identified. Five miRNAs (miR-151b, miR-151a-5p, let-7a-2-3p, miR-363-3p, miR-20b-5p) had prognostic significance in AML. The gene ontology analysis showed that upregulated DEGs suggested significant enrichment in MHC class II protein complex, extracellular structure organization, blood vessel development, cell morphogenesis involved in differentiation, embryonic morphogenesis, regulation of cell adhesion, and so on. Similarly, the downregulated DEGs were mainly enriched in secretory granule lumen, extracellular structure organization. In the gene set enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways, the RUNX1 mutation was associated with adherent junction, WNT signaling pathway, JAK-STAT signaling pathway, pathways in cancer, cell adhesion molecules CAMs, MAPK signaling pathway. Eleven genes (PPBP, APP, CCR5, HLA-DRB1, GNAI1, APLNR, P2RY14, C3AR1, HTR1F, CXCL12, GNG11) were simultaneously identified by hub gene analysis and module analysis. MicroRNA-363-3p may promote the development of RUNX1 mutation AML, targeting SPRYD4 and FNDC3B. In addition, the RUNX1 mutation rates in patient were obviously correlated with age, white blood cell, FAB type, risk(cyto), and risk(molecular) (P < .05).ConclusionOur findings have indicated that multiple genes and microRNAs may play a crucial role in RUNX1 mutation AML. MicroRNA-363-3p may promote the development of RUNX1 mutation AML by targeting SPRYD4 and FNDC3B.
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Project description:Macrophages (MΦ) and dendritic cells (DC) play a fundamental role in shaping immune responses by sensing a plethora of Pathogen Associated Molecular Patterns (PAMPs), phagocytosis and antigen presentation to T lymphocytes. These important biological processes require efficient cell movement and an intact cellular morphology for dynamic interaction. The role of microRNAs (miRs) in this regard, however, is not well understood. In the present study, we show that miR-30b and miR-142-3p regulate migration and morphology of MΦ and DC. Transient overexpression of miR-30b and miR-142-3p attenuates migration and these cells display unique morphological deformities observed under electron microscopy. In addition, miR-142-3p overexpression in MΦ impaired phagocytosis of FITC-conjugated latex beads using live microscopy imaging. Interestingly, live cell imaging and F-actin staining revealed marked changes in the cell polarity and actin polymerization status, respectively. To identify miR-142-3p regulated pathways, we profiled global transcriptome changes in miR-142-3p or control mimic transfected DC. Expression of several genes were differentially altered by miR-142-3p and were associated with pathways related to cell movement, cell adhesion, and cytoskeletal rearrangement. Bioinformatics analysis identified a significant subset of downregulated genes with one or more predicted miR-142-3p binding sites in their 3'UTR strongly suggesting direct post-transcriptional impact of these miRNAs on multiple transcripts. Using dual luciferase assays, novel miR-142-3p binding sites were validated for three genes (Vinculin, Dab2 and Skap2) directly associated with cytoskeletal rearrangement and cell movement. In summary, our results show that miR-30b and miR-142-3p are regulators of myeloid cell cytoskeletal homeostasis and morphology.
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Project description:Acute myeloid leukemia (AML) arises from a complex sequence of biological and finely orchestrated events that are still poorly understood. Increasingly, epigenetic studies are providing exciting findings that may be exploited in promising and personalized cutting-edge therapies. A more appropriate and broader screening of possible players in cancer could identify a master molecular mechanism in AML. Here, we build on our previously published study by evaluating a histone deacetylase (HDAC)2-mediated miRNA regulatory network in U937 leukemic cells. Following a comparative miRNA profiling analysis in genetically and enzymatically HDAC2-downregulated AML cells, we identified miR-96-5p and miR-92a-3p as potential regulators in AML etiopathology by targeting defined genes. Our findings support the potentially beneficial role of alternative physiopathological interventions.
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Project description:Autophagy is an important mechanism involved in the regulation of acute myeloid leukemia (AML) chemoresistance. The long noncoding RNA (lncRNA) differentiation antagonizing non-protein coding RNA (DANCR) exhibits oncogenic activity in several types of human cancers, including AML, but it remains unclear whether it regulates autophagy and chemoresistance in AML. We report here that cytarabine (Ara-C) treatment elevates DANCR expression in human AML cells. In addition, DANCR overexpression confers and its knockdown diminishes Ara-C resistance in human AML cells, suggesting that DANCR positively regulates AML chemoresistance to Ara-C. Moreover, DANCR promotes autophagy in Ara-C-treated human AML cells and acts as a sponge to decrease miR-20a-5p expression, thereby upregulating the expression of ATG16L1, a critical component of the autophagy machinery. Importantly, ATG16L1 silencing abrogates DANCR-promoted autophagy and markedly restores DANCR-conferred Ara-C resistance, suggesting that DANCR promotes MIR-874-3P/ATG16L1 axis-regulated autophagy to confer Ara-C resistance in human AML cells. Together, this study identifies DANCR as a positive regulator of Ara-C resistance in human AML cells, suggesting this lncRNA as a potential target for overcoming Ara-C resistance in AML chemotherapy.
| S-EPMC8024725 | biostudies-literature