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MiR-486 promotes proliferation and suppresses apoptosis in myeloid cells by targeting Cebpa in vitro.

ABSTRACT: The monocytic MDSC (M-MDSC) is one of the major types of MDSCs, which play important roles in suppression of antitumor immunity. However, the mechanisms underlying how M-MDSCs so heavily accumulate in patients with cancer are still poorly understood. The purpose of this study was to identify miRNAs that regulate the proliferation and differentiation of M-MDSCs. Microarray analysis was performed to identify differentially expressed miRNAs between tumor-induced M-MDSCs (TM-MDSCs) and their counterparts from tumor-free mice. The miRNAs and their target genes that regulate the proliferation and differentiation of myeloid cells were predicted by bioinformatics analysis and validated by RT-qPCR. Luciferase reporter assays were used to analyze the relationships between miRNAs and target genes. Overexpression of candidate miRNAs and target genes in myeloid cells was conducted to verify their functions in cell proliferation, differentiation, and apoptosis. Our data showed that miR-486 was overexpressed in TM-MDSCs. Cebpa was predicted to be one of the target genes of miR-486 that regulates the proliferation of myeloid cells. Expression of Cebpa was inversely correlated with miR-486 in TM-MDSCs, and we found that overexpression of miR-486 suppressed the expression of Cebpa in both 293T cells determined by luciferase reporter assays and in myeloid cells determined by RT-qPCR. Overexpression of miR-486 promoted proliferation and suppressed apoptosis in myeloid cells, as opposed to overexpression of Cebpa, which promoted the opposing phenotype. Overexpression of either miR-486 or Cebpa inhibited differentiation of myeloid cells. This study indicates that miR-486 promotes proliferation and suppresses apoptosis in myeloid cells by targeting Cebpa in vitro, suggesting that miR-486 and Cebpa might be involved in the expansion of TM-MDSCs in tumor-bearing mice.

SUBMITTER: Jiang J

PROVIDER: S-EPMC6143942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:CircLARP4 is reported to act as a tumor suppressor in some cancers. However, the detailed roles and molecular basis of circLARP4 in non-small cell lung cancer (NSCLC) tumorigenesis are still unclear. The aim of the study is to explore the potential roles and molecular basis of circLARP4 in NSCLC tumorigenesis. Materials and Methods:qRT-PCR was taken to detect circLARP4 and miR-135b expressions. MTT assay, ?transwell invasion assay and flow cytometry analysis were applied to evaluate cell proliferation, invasion and apoptosis, respectively. Glycolysis was assessed by measuring hexokinase2 (HK2) expression, glucose consumption and lactate production. Association between circLARP4 and miR-135a was examined by luciferase reporter and RIP assays. The changes of the phosphatase and tension homolog (PTEN)/protein kinase B (AKT)/hypoxia-inducible factor-1? (HIF-1?) pathway were evaluated by Western blot. The nude mouse xenograft models were applied to verify the regulation of circLARP4 in vivo. Results:CircLARP4 was decreased in NSCLC tissues and cells. CircLARP4 overexpression blocked cell proliferation and invasion, and facilitated apoptosis in NSCLC cells. Meanwhile, circLARP4 overexpression suppressed glycolysis in NSCLC cells, as evidenced by the reduced HK2, glucose consumption and lactate production levels. Further analyses proved a downregulation of miR-135b by circLARP4 in a ceRNA-dependent manner in NSCLC cells. CircLARP4-mediated tumor? suppression on NSCLC progression was partially overturned by overexpressing miR-135b. Moreover, we confirmed that circLARP4 had antitumor effect on xen?ograft tumors and downregulated miR-135b. Furthermore, circLARP4 overexpression inhibited the PTEN/AKT/HIF-1? pathway in NSCLC cells and xenograft tumors by downregulating miR-135b. Conclusion:Our findings suggested that ?circLARP4 suppressed NSCLC progression by sponging miR-135b through inactivation of the PTEN/AKT/HIF-1? pathway, which broadens our understanding concerning the roles of circLARP4 in NSCLC tumorigenesis.

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MiR-486 promotes proliferation and suppresses apoptosis in myeloid cells by targeting Cebpa in vitro.

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