Bortezomib Inhibits Multiple Myeloma Cells by Transactivating ATF3 to Trigger miR-135a-5p- Dependent Apoptosis.
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ABSTRACT:
SUBMITTER: Lai X
PROVIDER: S-EPMC8493032 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.
2019-11-12 | PXD009845 | Pride
Project description:Objectives: This research aimed to explore the role of miR-135a-5p in head and neck squamous cell carcinoma (HNSCC) cells and its influence on cell viability. Moreover, we aimed to compare effects of miR-135a-5p and miR-494 in HNSCC, which was found to repress HOXA10 expression in oral cancer. Methods: The association between miR-135a-5p and HOXA10 was confirmed by green fluorescence protein reporter assay and qRT-PCR. The expression levels of HOXA10 in HNSCC cell lines (CAL-27, FaDu and NEC) were examined using western blot. The expression levels of HOXA10 in FaDu cells and CAL-27 cells were examined by western blot after transfection with miR-135a-5p mimics and miR-494 mimics. Colony formation assay and flow cytometry assay were respectively utilized to detect the proliferation and apoptosis of HNSCC cells after transfection with HOXA10 plasmids and HOXA10-KO plasmids. In vitro tumor xenograft experiments were performed to analyze the inhibitive effect of miR-135a-5p on HOXA10 in BALA/c mice. Results: HOXA10 was overexpressed in HNSCC cells, while miR-135a-5p was under-expressed. Therefore, low expression of HOXA10 lengthened disease-free survival time and overall survival time. MiR-135a-5p overexpression could inhibit HOXA10 expression by directly targeting HOXA10 3'UTR, and the inhibition was more effective than miR-494. HOXA10 suppression inhibited proliferation and enhanced apoptosis of HNSCC cells. In vivo experiments showed that miR-135a-5p could decelerate the growth of tumor cells in mice by downregulating HOXA10 expression. Conclusion: MiR-135a-5p could repress HNSCC cells proliferation and enhance apoptosis by directly targeting HOXA10, implying miR-135a-5p's significance on HNSCC treatment.
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Project description:BackgroundMultiple myeloma (MM) accounts for 10% of all hematological malignancies. Dysregulation of microRNAs (miRNAs) or long non-coding RNAs (lncRNAs) has important impacts on progression of MM. Circular RNAs (circRNAs) are correlated with malignancy in the modulation of tumor progression. This study aims to investigate the effect of circ_0000190 on regulating the progression of MM.MethodMicroscopic examination via single molecule fluorescent in situ hybridization indicates the location of circ_0000190. qRT-PCR and Western blot were used to evaluate the expression of RNAs and proteins. Potential target of circ_0000190 was searched as miRNA, and examined by luciferase reporter assay. A computational screen was also conducted to search the potential target of miRNA. In vitro cell viability, proliferation, apoptosis assays and flow cytometric were performed to assess the effects of circ_0000190 and its target on MM. Mice model of human MM was established with subcutaneous xenograft tumor, qRT-PCR and western blot were performed to detect the underlying mechanisms of circ_0000190 on MM.ResultsCirc_0000190 was located in the cytoplasm, and down-regulated in both bone marrow tissue and peripheral blood, while the target of circ_0000190, miR-767-5p, was up-regulated, suggesting a negative correlation between them. The binding ability between circ_0000190 and miR-767-5p was confirmed by luciferase reporter assay. Moreover, circ_0000190 inhibited cell viability, proliferation and induced apoptosis of MM thus inhibiting cell progression, which is partially through the negative regulation of miR-767-5p. Mitogen-activated protein kinase 4 (MAPK4) is a direct target of miR-767-5p. In addition, over-expression of miR-767-5p promoted cell progression by directly targeting and regulating MAPK4. The MM model mice with administration of circ_0000190 suppressed tumor growth and progression.ConclusionOur results revealed that the ability of circ_0000190 to protect against MM was inherited through repression of miR-767-5p, and miR-767-5p might be a tumor drive through targeting MAPK4. Therefore, a novel role of circ_0000190 on regulating the progression of MM was found, and the clinical application of circRNAs might represent a strategy in MM.
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