MicroRNA-130b promotes cell migration and invasion by targeting peroxisome proliferator-activated receptor gamma in human glioma
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MicroRNAs (miRNAs) have recently been identified as a new class of short single-stranded endogenous RNA molecules (~22 nt in length). Although miRNAs were first discovered in Caenorhabditis elegans in 1993, it was only 10 years ago that they were identified in mammals. MiRNAs are highly conserved across species and it has been estimated that miRNAs may regulate up to 30% of all genes in the human genome. MiRNAs have critical functions in many diverse biological processes, including the regulation of stemness, cell proliferation, differentiation, and apoptosis. The miRNA 17-92 cluster has been suggested to play important roles in regulating renewal and/or differentiation of stem cells, including in ES cells and in other adult stem cells. However, the function of miRNAs in regulating spermatogonial stem cells (SSCs) is still unknown. In this study, we explored the expression, the role, and the targets of the miRNA 17-92 cluster in SSCs, specifically miRNA-20, miRNA-106a, and miRNA-93. Real-time PCR and fluorescent in situ hybridization revealed that miRNA-20 and miRNA-106a were abundantly expressed in mouse SSCs (GFRA1+ spermatogonia), whereas their expression decreased significantly in the differentiated c-kit+ spermatogonia, suggesting that miRNA-20 and miRNA-106a play a role in regulating renewal of the SSCs. MiRNA-93 was significantly lower in the SSCs compared to the differentiated spermatogonia, suggesting that miRNA-93 regulates differentiation. Using miRNA microarrays, we identified a list of miRNAs that were enriched in the SSCs compared to non-stem cells, e.g., Let-7G and Let-7I. To identify cell phenotype and genes regulated by a particular miRNA, we used mimics to miRNA-20, miRNA-106a, and miRNA-93, both in vitro and in vivo. The miRNA mimics are chemically synthesized RNA designed to mimic individual endogenous mature miRNAs. The mimics enter the miRNA-processing pathway and are treated identical to their endogenous counterpart. Semi-quantitative RT-PCR demonstrated that miRNA-20 and miRNA-106a mimics increased expression of PCNA and Plzf mRNA in the SSCs. In contrast, miRNA-20 and miRNA-106a inhibitors induced the expression of c-kit mRNA. These results further suggest that miRNA-20 and miRNA-106a may be involved in renewal of SSCs. Using software prediction and an in vitro study, we demonstrated that Stat3 is a target of miRNA-20 and miRNA-106a. We next examined the role of these miRNAs in vivo using mimics transfected into the GFRA1+ SSCs. These miRNA-transfected stem cells were then transplanted into seminiferous tubules of sterile busulfan treated mice. The miRNA-20 and miRNA-106a mimics increased significantly the number of SSCs in the testes of the busulfan treated mice, compared to controls, when analyzed by immunohistochemistry after 60 days. Our study provides novel insights into the endogenous small RNA molecules that regulate SSCs and has important implications on offering new therapeutic targets for the treatment of male infertility as well as a novel approach for the treatment of male contraception. (platform)
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Abstract Glioma is the most common and fatal primary brain tumour with poor prognosis; however, the functional roles of miRNAs in glioma malignant progression are insufficiently understood. Here, we used an integrated approach to identify miRNA functional targets during glioma malignant progression by combining the paired expression profiles of miRNAs and mRNAs across 160 Chinese glioma patients, and further constructed the functional miRNA–mRNA regulatory network. As a result, most tumour-suppressive miRNAs in glioma progression were newly discovered, whose functions were widely involved in gliomagenesis. Moreover, three miRNA signatures, with different combinations of hub miRNAs (regulations≥30) were constructed, which could independently predict the survival of patients with all gliomas, high-grade glioma and glioblastoma. Our network-based method increased the ability to identify the prognostic biomarkers, when compared with the traditional method and random conditions. Hsa-miR-524-5p and hsa-miR-628-5p, shared by these three signatures, acted as protective factors and their expression decreased gradually during glioma progression. Functional analysis of these miRNA signatures highlighted their critical roles in cell cycle and cell proliferation in glioblastoma malignant progression, especially hsa-miR-524-5p and hsa-miR-628-5p exhibited dominant regulatory activities. Therefore, network-based biomarkers are expected to be more effective and provide deep insights into the molecular mechanism of glioma malignant progression.
Gene regulatory network
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Glioma is a common tumor of the nervous system.In some gliomas, some of the expressions of microRNA are up-regulated.Some of them are down regulated.Some microRNA expressions promote the development of gliomas, while some microRNA exert inhibitory effects.MicroRNA is a small species, which is quite conservative in the evolution of species.It degrades messenger RNA or impedes its translation by guiding the silencing complex with target gene messenger RNA base pairs.Therefore, by studying the expression of microRNA in glioma, we can not only provide evidence for early diagnosis of glioma, but also provide a new plan for clinical treatment of glioma.By reading the literature, the expression of microRNA in glioma, the target of action and its effect on the biological characteristics of glioma were reviewed.
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Glioma; MicroRNA; Review
RNA Silencing
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A growing body of evidence suggests that microRNA-592 is involved in tumor initiation and development in several types of human cancers. However, the biological functions and molecular mechanism of microRNA-592 in glioma remain unclear. In this study, we explored the potential role of microRNA-592 in glioma as well as the possible molecular mechanisms. Our results proved that microRNA-592 expression was significantly downregulated in glioma tissues and cell lines (p < 0.01). Functional assays revealed that overexpression of microRNA-592 dramatically reduced the cell proliferation, migration, and invasion and induced cell arrest at G1/G0 phase in vitro. Mechanistic investigations defined insulin-like growth factor binding protein 2 as a direct and functional downstream target of microRNA-592, which was involved in the microRNA-592-mediated tumor-suppressive effects in glioma cells. Moreover, the in vivo study showed that microRNA-592 overexpression produced the smaller tumor volume and weight in nude mice. In summary, these results elucidated the function of microRNA-592 in glioma progression and suggested a promising application of it in glioma treatment.
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Glioblastoma multiforme is the most deadly primary brain tumor and has no effective treatment. Therefore, it is important to identify novel and effective therapies that impede glioma tumorigenesis. MicroRNAs (miRNAs) are helpful analytical biomarkers and may be useful targets for treating multiple human cancers. Previous reports suggest that miRNA-485-5p is dysregulated and contributes to tumorigenesis in some cancer types. Nevertheless, the biological role of miRNA-485-5p in glioma is not well understood. In this study, we demonstrated that miRNA-485-5p expression was reduced in gliomat issues and cell lines. In addition, miRNA-485-5p overexpression inhibited cell proliferation, migration, and invasion in glioma cell lines. Additionally, we identified Tumor Protein D52 Like 2 (TPD52L2) as a direct target of miRNA-485-5p. Moreover, we showed that miRNA-485-5p regulated glioma tumorigenesis by down-regulating TPD52L2 expression in vitro and in vivo. Our results suggest that miRNA-485-5p is a suppressor of glioma tumorigenesis and could serve as a novel candidate for therapeutic applications in glioma treatment.
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In recent years, a large amount of research has reported that microRNA (miRNA) dysregulation is closely related to glioma progression. miR-524, a member of the miRNA family, has been confirmed to be involved in many human diseases, including glioma. However, the role and molecular mechanism of miR-524 in glioma have not been clarified. In our study, we showed that miR-524 expression was significantly decreased in glioma and was associated with glioma recurrence. Next, we performed a series of assays and confirmed that the upregulation of miR-524 suppressed glucose uptake, proliferation, migration and invasion in glioma cell lines. Then, through bioinformatics software and a dual luciferase assay, we demonstrated that NCF2 was a target gene of miR-524. In addition, we found that NCF2 reintroduction restored the inhibitor effect of miR-524 on glioma progression. These results elucidate the mechanism of miR-524 in glioma development and provide a potential therapeutic strategy for glioma patients.
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Glioma accounts for the majority of primary malignant brain tumors in adults and is highly aggressive. Although various therapeutic approaches have been applied, outcomes of glioma treatment remain poor. MicroRNAs are a class of small noncoding RNAs that function as regulators of gene expression. Accumulating evidence shows that microRNAs are associated with tumorigenesis and tumor progression. In this study, we found that miR-105 is significantly downregulated in glioma tissues and glioma cell lines. We identified suppressor of Zeste 12 homolog as a novel direct target of miR-105 and showed that suppressor of Zeste 12 homolog protein levels were inversely correlated with the levels of miR-105 expression in clinical specimens. Overexpression of miR-105 inhibited cell proliferation, tumorigenesis, migration, invasion, and drug sensitivity, whereas overexpression of suppressor of Zeste 12 homolog antagonized the tumor-suppressive functions of miR-105. Taken together, our results indicate that miR-105 plays a significant role in tumor behavior and malignant progression, which may provide a novel therapeutic strategy for the treatment of glioma and other cancers.
Tumor progression
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Emerging studies revealed that a poor intrauterine environment elicited by maternal nutrient restriction (MNR) is associated with an increased risk of metabolic diseases in adulthood. Previous research has shown that microRNAs (miRNAs) exert pivotal roles in modulating molecular pathways involved in disease pathogenesis and progression. In this respect, we herein examined miRNA profiles in samples of liver from offspring whose mothers were fed either with a 50% food-restricted diet or standard laboratory chow during pregnancy. Our findings enumerated that miR-181a, involved in lipid metabolism, was found to be downregulated in the liver of MNR offspring at 1 day of age when compared to that of control offspring. We also noted that overexpression of miR-181a reduced the lipid droplets after treatment with oleic acid for 48 h, which suppressed the expressions levels of SIRT1, FOXO1, KLF6 and PPARγ in BRL-3A cells, while the opposite results were observed with decreased expression of miR-181a. Furthermore, the luciferase reporter assay confirmed the direct interactions between miR-181a with KLF6 and SIRT1. In adults, the MNR offspring elucidated increased TG content, decreased expression of miR-181a, and increased expressions levels of SIRT1, FOXO1, KLF6, and PPARγ in liver tissues. Collectively, these findings provided novel evidence that MNR could regulate miRNAs expression, which might be related to lipid metabolism in MNR offspring.
Pathogenesis
FOXO1
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Reprogramming
Homeobox protein NANOG
KLF4
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