MicroRNA-149 targets caspase-2 in glioma progression.
Ontology highlight
ABSTRACT:
SUBMITTER: Shen X
PROVIDER: S-EPMC5041987 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Metastasis is the predominant cause of death in breast cancer patients. Several lines of evidence have shown that microRNAs (miRs) can have an important role in cancer metastasis. Using isogenic pairs of low and high metastatic lines derived from a human breast cancer line, we have identified miR-149 to be a suppressor of breast cancer cell invasion and metastasis. We also identified GIT1 (G-protein-coupled receptor kinase-interacting protein 1) as a direct target of miR-149. Knockdown of GIT1 reduced migration/invasion and metastasis of highly invasive cells. Re-expression of GIT1 significantly rescued miR-149-mediated inhibition of cell migration/invasion and metastasis. Expression of miR-149 impaired fibronectin-induced focal adhesion formation and reduced phosphorylation of focal adhesion kinase and paxillin, which could be restored by re-expression of GIT1. Inhibition of GIT1 led to enhanced protein degradation of paxillin and ?5?1 integrin via proteasome and lysosome pathways, respectively. Moreover, we found that GIT1 depletion in metastatic breast cancer cells greatly reduced ?5?1-integrin-mediated cell adhesion to fibronectin and collagen. Low level of miR-149 and high level of GIT1 was significantly associated with advanced stages of breast cancer, as well as with lymph node metastasis. We conclude that miR-149 suppresses breast cancer cell migration/invasion and metastasis by targeting GIT1, suggesting potential applications of the miR-149-GIT1 pathway in clinical diagnosis and therapeutics.
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Project description:Colorectal cancer (CRC) has developed into the third leading cause of cancer-associated death worldwide. Studies have confirmed that circular RNAs (circRNAs) absorb microRNAs (miRNAs) to regulate the function of downstream genes. This study aimed to explore the underlying mechanism of circRNA 100146 in CRC. The expression of circRNA 100146, miRNA 149 (miR-149), and high mobility group AT-Hook 2 (HMGA2) was detected by quantitative real-time PCR (RT-qPCR). A series of biofunctional effects (cell viability, apoptosis, migration/invasion) were evaluated by the use of methyl thiazolyl tetrazolium (MTT), flow cytometry, and transwell assays. Protein levels were measured by Western blot assay. A xenograft model was established for in vivo experiments. The interactions among circRNA 100146, miR-149, and HMGA2 were evaluated by dual-luciferase reporter assay, RNA immunoprecipitation assays, or RNA pulldown assay. circRNA 100146 was upregulated in CRC tissues and cells. circRNA 100146 knockdown inhibited cell proliferation, promoted apoptosis, and suppressed migration and invasion in vitro and impeded tumor growth in vivo Also, miR-149 was negatively regulated by circRNA 100146 and was targeted to HMGA2 and mediated its expression. Moreover, miR-149 interference abrogated the activities of silenced circRNA 100146 in proliferation, apoptosis, migration, and invasion. Furthermore, HMGA2 overexpression abated the effects described above caused by circRNA 100146 silencing, while the mutations on miR-149 binding sites in the 3' untranslated region (3'-UTR) of HMGA2 led to its loss of this ability. circRNA 100146 knockdown repressed proliferation, enhanced apoptosis, and hindered migration and invasion in SW620 and SW480 cells through targeting the miR-149/HMGA2 axis.
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Project description:BackgroundThe Polycomb Repressor Complex (PRC) is an epigenetic regulator of transcription whose action is mediated by 2 protein complexes, PRC1 and PRC2. PRC is oncogenic in glioblastoma, where it is involved in cancer stem cell maintenance and radioresistance.MethodsWe used a set of glioblastoma patient samples, glioma stem cells, and neural stem cells from a mouse model of glioblastoma. We characterized gene/protein expression and cellular phenotypes by quantitative PCR/Western blotting and clonogenic, cell-cycle, and DNA damage assays. We performed overexpression/knockdown studies by lentiviral infection and microRNA/small interfering RNA oligonucleotide transfection.ResultsWe show that microRNA-128 (miR-128) directly targets mRNA of SUZ12, a key component of PRC2, in addition to BMI1, a component of PRC1 that we previously showed as a target as well. This blocks the partially redundant functions of PRC1/PRC2, thereby significantly reducing PRC activity and its associated histone modifications. MiR-128 and SUZ12/BMI1 show opposite expression in human glioblastomas versus normal brain and in glioma stemlike versus neural stem cells. Furthermore, miR-128 renders glioma stemlike cells less radioresistant by preventing the radiation-induced expression of both PRC components. Finally, miR-128 expression is significantly reduced in neural stem cells from the brain of young, presymptomatic mice in our mouse model of glioblastoma. This suggests that loss of miR-128 expression in brain is an early event in gliomagenesis. Moreover, knockdown of miR-128 expression in nonmalignant mouse and human neural stem cells led to elevated expression of PRC components and increased clonogenicity.ConclusionsMiR-128 is an important suppressor of PRC activity, and its absence is an early event in gliomagenesis.
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Project description:An increasing body of evidence indicates that miR-149 can both suppress and promote tumor growth depending on the tumor type. However, the role of miR-149 in the progression of gastric cancer (GC) remains unknown. Here we report that miR-149 is a tumor suppressor in human gastric cancer. miR-149 expression is decreased in GC cell lines and clinical specimens in comparison to normal gastric epithelial cell and tissues, respectively. The expression levels of miR-149 also correlate with the differentiation degree of GC cells and tissues. Moreover, ectopic expression of miR-149 in gastric cancer cells inhibits proliferation and cell cycle progression by down-regulating ZBTB2, a potent repressor of the ARF-HDM2-p53-p21 pathway, with a potential binding site for miR-149 in its mRNA's 3'UTR. It is also found that ZBTB2 expression increases in GC cells and tissues compared to normal gastric epithelial cell and tissues, respectively. Silencing of ZBTB2 leads to suppression of cell growth and cell cycle arrest in G0/G1 phase, indicating that ZBTB2 may act as an oncogene in GC. Furthermore, transfection of miR-149 mimics into gastric cancer cells induces down-regulation of ZBTB2 and HDM2, and up-regulation of ARF, p53, and p21 compared to the controls. In summary, our data suggest that miR-149 functions as a tumor suppressor in human gastric cancer by, at least partially through, targeting ZBTB2.
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Project description:BackgroundmiRNAs have been reported to be involved in multiple biological processes of gliomas. Here, we aimed to analyze miR-4310 and its correlation genes involved in the progression of human glioma.MethodsmiR-4310 expression levels were examined in glioma and non-tumor brain (NB) tissues. The molecular mechanisms of miR-4310 expression and its effects on cell proliferation, migration, and invasion were explored using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide, Transwell chamber, Boyden chamber, and western blot analyses, as well as its effect on tumorigenesis was explored in vivo in nude mice. The relationships between miR-4310, SP1, phosphatase, and tensin homolog (PTEN) were explored using chromatin immunoprecipitation, agarose gel electrophoresis, electrophoresis mobility shift, and dual-luciferase reporter gene assays.ResultsmiR-4310 expression was upregulated in glioma tissues compared to that in NB tissues. Overexpressed miR-4310 promoted glioma cell proliferation, migration, and invasion in vitro, as well as tumorigenesis in vivo. The inhibition of miR-4310 expression was sufficient to reverse these results. Mechanistic analyses revealed that miR-4310 promoted glioma progression through the PI3K/AKT pathway by targeting PTEN. Additionally, SP1 induced the expression of miR-4310 by binding to its promoter region.ConclusionmiR-4310 promotes the progression of glioma by targeting PTEN and activating the PI3K/AKT pathway; meanwhile, the expression of miR-4310 was induced by SP1.
| S-EPMC7745362 | biostudies-literature
Project description:MicroRNA (miR)?mediated mRNA and multiple signaling pathway dysregulations have been extensively implicated in several cancer types, including gliomas. Although previous studies have reported that miR?301a acts as an oncogene, the underlying mechanisms of miR?301a in the initiation and progression of glioma remain unknown. The present study aimed to investigate the involvement of miR?301a?mediated signaling pathway dysregulation in glioma. The results identified that miR?301a was significantly upregulated in gliomas and was associated with a poor prognosis based on The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. Moreover, zinc and ring finger 3 (ZNRF3) exerted a critical role in the miR?301a?mediated effects on the malignant phenotype, such as by affecting proliferation and apoptosis. Mechanistically, the TOP/FOP luciferase assay, western blotting and immunofluorescence results demonstrated that miR?301a knockdown inhibited the wnt/??catenin signaling pathway, at least partially via ZNRF3, while ZNRF3 was a direct functional target of miR?301a, as indicated by luciferase reporter assay and western blot analysis. Furthermore, ZNRF3 could in turn repress miR?301a expression, which was dependent on the wnt pathway. Collectively, the present study identified a novel miR?301a/ZNRF3/wnt/??catenin signaling feedback loop that serves critical roles in glioma tumorigenesis, and that may represent a potential therapeutic target.
| S-EPMC7721082 | biostudies-literature
Project description:BackgroundGlioblastoma is an extraordinarily aggressive disease that requires more effective therapeutic options. Snail family zinc finger 1, dysregulated in many neoplasms, has been reported to be involved in gliomas. However, the biological mechanisms underlying SNAI1 function in gliomas need further investigation.MethodsQuantitative real-time PCR was used to measure microRNA-128 (miR-128) expression level and western blot was performed to detect protein expression in U87 and U251 cells and human brain tissues. Cell cycle, CCK-8, transwell and wound-healing assays were performed. Dual-luciferase reporter assay was used for identifying the mechanism of SNAI1 and miR-128b regulation. The mechanism of miR-128 targeting SP1 was also tested by luciferase reporter assay. Immunohistochemistry and in situ hybridisation staining were used for quantifying SNAI1, SP1 and miR-128 expression levels in human glioma samples.ResultsThe Chinese Glioma Genome Atlas (CGGA) data revealed that SNAI1 was up-regulated in glioma and we confirmed the findings in normal and glioma tissues. SNAI1 depletion by shRNA retarded the cell cycle and suppressed proliferation and invasion in glioma cell lines. The CGGA data showed that the Pearson correlation index between SNAI1 and miR-128 was negatively correlated. SNAI1 suppressed miR-128b expression by binding to the miR-128b specific promoter motif, and miR-128 targeted SP1 via binding to the 3'-untranslated region of SP1. Moreover, introduction of miR-128 anti-sense oligonucleotide alleviated the cell cycle retardation, proliferation and invasion inhibition induced by SNAI1 shRNA. Immunohistochemistry and in situ hybridisation analysis of SNAI1, SP1 and miR-128 unraveled their expression levels and correlations in glioma samples.ConclusionsWe propose that the SNAI1/miR-128/SP1 axis, which plays a vital role in glioma progression, may come to be a clinically relevant therapeutic target.
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Project description:miRNA-184 is an oncogene in human hepatocellular carcinoma but acts as a tumor suppressor in tongue squamous cell carcinoma. Studies have shown that miR-184 was down-regulated in glioma and TNFα-induced protein 2 (TNFAIP2) was closely related to tumorigenesis. This study aimed to determine the functions of miR-184 in glioma and the mechanisms of miRNA-184-TNFAIP2 mediated glioma progression.Real-time reverse-transcription PCR detected expression of miR-184 and TNFAIP2. U87 and U251 cells were transfected with miR-184 mimic, inhibitor, or negative control miRNA, and their invasion abilities were assayed. Cellular proliferation was measured by the cell counting kit-8 assay. miR-184 effects on glioma cell apoptosis and cell cycle were assessed by flow cytometer. Biological information software have predicted that miR-184 could target TNFα-induced protein 2 (TNFAIP2), Which was further validated by Western blot and qRT-PCR in glioma cells. In vivo, U87 cells transduced with either lentiviral over-expressed miR-184 or control lentivirus were injected into nude mice subcutaneously and intracranial respectively.Expression of miR-184 was significantly lower in glioma tissues and cell-lines compared to normal brain tissues. Protein and mRNA expression of TNFAIP2 were inversely correlated with miR-184 in glioma. In vitro, proliferation and invasion abilities were also decreased in U87 and U251 cells after transfection with miR-184 mimic. In vivo, the xenografted tumor size in the miR-184 overexpressing group were smaller than the miR-NC group. Concordantly, U87 and U251 cells transfected with miR-184 mimic had a higher apoptosis rate, triggering an accumulation of cells at the G0/G1 phase and decreased cells in S-phase.miR-184 could regulate TNFAIP2 expression and affected its translation in glioma. miR-184 could also inhibit glioma progression and might serve as a novel therapeutic target in glioma.
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Project description:MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs that function as negative regulators of gene expression. They are transcribed from endogenous DNA and form hairpin structures (termed as pre-miRNAs) that are processed to form mature miRNAs. It remains largely unknown as to the molecular consequences of the natural genetic variation in pre-miRNAs. Here, we report that an A→G polymorphism (rs71428439) is located in Homo sapiens miR-149 stem-loop region. This polymorphism results in a change in the structure of the miR-149 precursor. Our results showed that the genotype distribution of this polymorphism in myocardial infarction cases was significantly different from that in the control subjects. We examined the biological significance of this polymorphism on the production of mature miR-149, and we observed that the G-allelic miR-149 precursor displayed a lower production of mature miR-149 compared with the A-allelic one. Further investigations disclosed that miR-149 could withstand mitochondrial fission and apoptosis through targeting the pro-apoptotic factor p53-up-regulated modulator of apoptosis (Puma). Enforced expression of miR-149 promoted cell survival, whereas knockdown of miR-149 rendered cells to be sensitive to apoptotic stimulation. Intriguingly, the A to G variation led pre-miR-149 to elicit an attenuated effect on the inhibition of mitochondrial fission and apoptosis. Finally, this polymorphism exerts its influence on cardiac function in the mouse model of myocardial infarction. These data suggest that this polymorphism in the miR-149 precursor may result in important phenotypic traits of myocardial infarction. Our findings warrant further investigations on the relationship between miR-149 polymorphism and myocardial infarction.
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Project description:MicroRNA-219-5p (miR-219-5p) is a key post-transcriptional regulator of gene expression that is known to regulate cancer progression, but its role in the context of hepatocellular carcinoma (HCC) remains to be fully elucidated. Herein, it was found that this miRNA functions as a tumor suppressor. Specifically, significant decreases in miR-219-5p expression were detected in HCC cells and patient serum samples relative to that found in the serum of 15 healthy people, and it was concluded that miR-219-5p overexpression was sufficient to impair HCC cell proliferation in vitro and vivo and migration in vitro. At the mechanistic level, it was found that miR-219-5p was able to suppress the expression of NEK6 (never in mitosis gene a-related kinase 6), thereby resulting in dysregulated β-catenin/c-Myc-regulated gene expression. When NEK6 was overexpressed in HCC cells, this was sufficient to reverse the inhibitory impact of miR-219-5p on HCC cell proliferation both in vitro and vivo and metastasis in vitro. Bioinformatics analyses were also conducted, and both miR-219-5p and Nek6 were linked to disease progression in HCC patients with advanced disease. More importantly, the serum specimen data showed that reduced perioperative plasma miR-219-5p correlated significantly with increased risk of early recurrence after curative hepatectomy, whereas it was opposed to NEK6. Together, these findings highlight miR-219-5p as a potentially valuable diagnostic biomarker that can potentially be leveraged to improve clinical outcomes in HCC patients.
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