Low-dose irradiation promotes Rad51 expression by down-regulating miR-193b-3p in hepatocytes.
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ABSTRACT:
SUBMITTER: Lee ES
PROVIDER: S-EPMC4880923 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Preeclampsia (PE) is a leading cause of maternal mortality worldwide. Several studies have detected some differentially expressed microRNAs in the preeclamptic placenta, but few of the identified microRNAs demonstrated consistent findings among different research studies. In this study, high-throughput microRNA sequencing (HTS) of 9 preeclamptic and 9 normal placentas was performed. Seventeen microRNAs were identified to be up-regulated, and 8 down-regulated in preeclamptic placentas. Eight differentially expressed microRNAs except one identified in our study were determined to be consistent with at least one previous study, while sixteen were newly found. We performed qRT-PCR with independent 22 preeclamptic placentas and 20 control placentas to verify the differentially expressed microRNAs, and ten microRNAs were validated. The predicted target genes of the aberrantly expressed miR-193b-3p were enriched in the following gene ontology categories: cell motility and migration, cell proliferation and angiogenesis. We also found that miR-193b-3p significantly decreased the migration and invasion of trophoblast (HTR-8/SVneo) cells and that miR-193b-3p could regulate trophoblasts migration and invasion through binding onto the 3'UTR target site of TGF-?2. In conclusion, we identified a list of differentially expressed microRNAs in PE placentas by HTS and provided preliminary evidence for the role of miR-193b-3p in the pathogenesis of preeclampsia.
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Project description:Radiation-induced central nervous system toxicity is a significant risk factor for patients receiving cancer radiotherapy. Surprisingly, the mechanisms responsible for the DNA damage-triggered neuronal cell death following irradiation have yet to be deciphered. Using primary cortical neuronal cultures in vitro, we demonstrated that X-ray exposure induces the mitochondrial pathway of intrinsic apoptosis and that miR-23a-3p plays a significant role in the regulation of this process. Primary cortical neurons exposed to irradiation show the activation of DNA-damage response pathways, including the sequential phosphorylation of ATM kinase, histone H2AX, and p53. This is followed by the p53-dependent up-regulation of the pro-apoptotic Bcl2 family molecules, including the BH3-only molecules PUMA, Noxa, and Bim, leading to mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome c, which activates caspase-dependent apoptosis. miR-23a-3p, a negative regulator of specific pro-apoptotic Bcl-2 family molecules, is rapidly decreased after neuronal irradiation. By increasing the degradation of PUMA and Noxa mRNAs in the RNA-induced silencing complex (RISC), the administration of the miR-23a-3p mimic inhibits the irradiation-induced up-regulation of Noxa and Puma. These changes result in an attenuation of apoptotic processes such as MOMP, the release of cytochrome c and caspases activation, and a reduction in neuronal cell death. The neuroprotective effects of miR-23a-3p administration may not only involve the direct inhibition of pro-apoptotic Bcl-2 molecules downstream of p53 but also include the attenuation of secondary DNA damage upstream of p53. Importantly, we demonstrated that brain irradiation in vivo results in the down-regulation of miR-23a-3p and the elevation of pro-apoptotic Bcl2-family molecules PUMA, Noxa, and Bax, not only broadly in the cortex and hippocampus, except for Bax, which was up-regulated only in the hippocampus but also selectively in isolated neuronal populations from the irradiated brain. Overall, our data suggest that miR-23a-3p down-regulation contributes to irradiation-induced intrinsic pathways of neuronal apoptosis. These regulated pathways of neurodegeneration may be the target of effective neuroprotective strategies using miR-23a-3p mimics to block their development and increase neuronal survival after irradiation.
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Project description:As a well-known cancer-related miRNA, miR-193b-3p is enriched in skeletal muscle and dysregulated in muscle disease. However, the mechanism underpinning this has not been addressed so far. Here, we probed the impact of miR-193b-3p on myogenesis by mainly using goat tissues and skeletal muscle satellite cells (MuSCs), compared with mouse C2C12 myoblasts. miR-193b-3p is highly expressed in goat skeletal muscles, and ectopic miR-193b-3p promotes MuSCs proliferation and differentiation. Moreover, insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) is the most activated insulin signaling gene when there is overexpression of miR-193b-3p; the miRNA recognition element (MRE) within the IGF1BP1 3' untranslated region (UTR) is indispensable for its activation. Consistently, expression patterns and functions of IGF2BP1 were similar to those of miR-193b-3p in tissues and MuSCs. In comparison, ectopic miR-193b-3p failed to induce PAX7 expression and myoblast proliferation when there was IGF2BP1 knockdown. Furthermore, miR-193b-3p destabilized IGF2BP1 mRNA, but unexpectedly promoted levels of IGF2BP1 heteronuclear RNA (hnRNA), dramatically. Moreover, miR-193b-3p could induce its neighboring genes. However, miR-193b-3p inversely regulated IGF2BP1 and myoblast proliferation in the mouse C2C12 myoblast. These data unveil that goat miR-193b-3p promotes myoblast proliferation via activating IGF2BP1 by binding to its 3' UTR. Our novel findings highlight the positive regulation between miRNA and its target genes in muscle development, which further extends the repertoire of miRNA functions.
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Project description:BackgroundPancreatic cancer (PC) is a highly lethal malignancy that requires effective novel therapies. M2 macrophages are abundant in the PC microenvironment and promote cancer progression. Exosomes are emerging mediators of the crosstalk between cancer cells and the microenvironment. This study was conducted to explore the role of M2 macrophage-derived exosomes in PC.MethodsExosomes derived from M2 macrophages were extracted. miR-193b-3p and TRIM62 were overexpressed or silenced to examine their function in PC. Luminescence assays were used to investigate the interaction between miR-193b-3p and TRIM62. Cell proliferation was examined by EdU staining. Would healing and transwell assays were applied to evaluate cell migration and invasion. Co-immunoprecipitation was used to assess the interaction between TRIM62 and c-Myc. Gene and protein expressions were analyzed by quantitative RT-PCR and immunoblotting, respectively.ResultsM2 macrophage-derived exosomal miR-193b-3p promoted the proliferation, migration, invasion, and glutamine uptake of SW1990 cells. Mechanism study revealed that TRIM62 is a target of miR-193b-3p. TRIM62 inhibited the proliferation, migration, invasion, and glutamine uptake of SW1990 cells by promoting c-Myc ubiquitination. Our data also suggested that TRIM62 expression negatively correlated with miR-193b-3p and c-Myc expression. High-expression of miR-193b-3p and c-Myc predicts poor prognosis, whereas low-expression of TRIM62 predicts poor prognosis in patients with PC.ConclusionM2 macrophage-derived exosomal miR-193b-3p enhances the proliferation, migration, invasion, and glutamine uptake of PC cells by targeting TRIM62, resulting in the decrease of c-Myc ubiquitination. This study not only reveals the mechanism underlying the crosstalk between M2 macrophages and PC cells but also suggests a promising therapeutic target for PC.
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Project description:Polo-like kinase 1 (PLK1) is a critical regulator of cell cycle progression and apoptosis. However, its regulation remains poorly understood. In the present study, we investigated the molecular mechanism underlying the post-transcriptional regulation of PLK1. We observed that heterogeneous nuclear ribonucleoprotein K (hnRNPK) and PLK1 were positively associated in several different cancers and high expression levels of them correlated with poor prognosis in patients with cancer. Knockdown of hnRNPK resulted in reduced expression of PLK1, whereas conversely, PLK1 expression was increased in hnRNPK-overexpressing cells. We found that hnRNPK regulated PLK1 expression through KH1- and KH2-dependent interactions with the 3'UTR of PLK1 mRNA. In addition, microRNA-149-3p (miR-149-3p) and miR-193b-5p suppressed PLK1 expression by targeting the 3'UTR of PLK1 mRNA. MicroRNA-elicited enrichment of PLK1 mRNA in Ago2 immunoprecipitation was altered by the presence or absence of hnRNPK. Furthermore, the deletion of the cytosine (C)-rich sequences of the 3'UTR of PLK1 mRNA abolished the decreased PLK1 expression observed via hnRNPK silencing and administration of miRNAs, a finding that suggests that hnRNPK shares this C-rich motif with miR-149-3p and miR-193b-5p. We also found that downregulation of PLK1 by either silencing hnRNPK or overexpression of miR-149-3p and miR-193b-5p decreased clonogenicity and induced apoptosis. Our findings from this study demonstrate that hnRNPK regulates PLK1 expression by competing with the PLK1-targeting miRNAs, miR-149-3p and miR-193b-5p.
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Project description:Background:The aim of the present study was to investigate the effect of over-expressing circular RNA (circ_0003645) on cell functions and its molecular mechanism in breast cancer. Methods:The expression profile of circ_0003645, breast cancer cell lines, and the transcription levels of circular RNA, miRNA and HMGB1 gene were detected by qRT-PCR. Flow cytometry analysis was manipulated to evaluate cancer cell proliferation and cell apoptosis. The correlation between miR-139p-3p and circular_0003645 or HMGB1 was predicted by GEO, and TCGA was confirmed using the dual-luciferase reporter assay. Results:Circ_0003645 expression was conspicuously increased in both the breast cancer tissues and cell lines. Circ_0003645 knockdown inhibited cell proliferation and induced the apoptosis of breast cancer cells in vitro and in vivo. By sponging miR-139-3p, circ_0003645 promoted the breast cancer cells progression and positively regulated HMGB1 gene. Conclusion:Circ_0003645 functions as a ceRNA for miR-139-3p, which could upregulate HMGB1 and further promote cell proliferation in breast cancer.
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Project description:Glioma-associated microglial cells, a key component of the tumor microenvironment, play an important role in glioma progression. In this study, the mouse glioma cell line GL261 and the mouse microglia cell line BV2 were chosen. First, circadian gene expression in glioma cells co-cultured with either M1 or M2 microglia was assessed and the exosomes of M2-polarized and unpolarized BV-2 microglia were extracted. Subsequently, we labeled the exosomes with PKH67 and treated GL261 cells with them to investigate the exosome distribution. GL261 cell phenotypes and related protein expression were used to explore the role of M2 microglial exosomes in gliomas. Then a specific miR-7239-3p inhibitor was added to verify miR-7239-3p functions. Finally, the mouse subcutaneous tumorigenic model was used to verify the tumorigenic effect of M2 microglial exosomes in vivo. Our results showed that in gliomas co-cultured with M2 microglia, the expression of the BMAL1 protein was decreased (P < 0.01), while the expression of the CLOCK protein was increased (P < 0.05); opposite results were obtained in gliomas co-cultured with M1 microglia. After treatment with M2 microglial exosomes, the apoptosis of GL261 cells decreased (P < 0.001), while the viability, proliferation, and migration of GL261 cells increased. Increased expression of N-cadherin and Vimentin, and decreased E-cadherin expression occurred upon treatment with M2 microglial exosomes. Addition of an miR-7239-3p inhibitor to M2 microglial exosomes reversed these results. In summary, we found that miR-7239-3p in the glioma microenvironment is recruited to glioma cells by exosomes and inhibits Bmal1 expression. M2 microglial exosomes promote the proliferation and migration of gliomas by regulating tumor-related protein expression and reducing apoptosis.
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