Chlorotoxin fusion protein regulates miR-374a and TNFAIP8 expression and inhibits glioma cell proliferation and promotes apoptosis.
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ABSTRACT:
SUBMITTER: Yuan Z
PROVIDER: S-EPMC7547943 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Accumulating evidence suggests that microRNAs (miRNAs) play a key role in the biological behaviors and progression of glioma. However, the function and bio‑molecular mechanisms of miR‑342 in glioma remain largely unclear. In the present study, reverse transcription quantitative‑polymerase chain reaction and western blotting were performed to determine the mRNA and protein expression levels of the factors investigated. MTT assay was performed to examine the proliferation rates. Luciferase reporter assay was performed to test the binding between miRNA‑342 and its putative target. Data indicated that miR‑342 expression was markedly decreased in human glioma tissues and cell line U87, and reduced miR‑342 expression significantly promoted cell proliferation. In order to explore the mechanisms, G‑protein coupled receptor family C group 5 member A (GPRC5A) was identified as a target of miR‑342 and depletion of GPRC5A suppressed cell proliferation. Our findings demonstrated that miR‑342 regulates the cell proliferation of glioma by targeting GPRC5A, which indicates that miR‑342 is a target of interest regarding the treatment of refractory glioma, and it may provide a promising prognostic and therapeutic strategy for glioma treatment.
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Project description:Glioma is the most general primary and lethal intracranial malignant tumor. Pterostilbene (PTE), an analog of stilbene and resveratrol, has attracted attention in recent years due to its significant antitumor activity in multiple solid tumors; however, its effect on drug-resistant glioma cells and the underlying mechanism have not yet been reported. In this study, we found that pterostilbene inhibited proliferation, induced intrinsic mitochondria-mediated apoptosis and caused S phase arrest, inhibited migration and excessive invasion in glioma cells. Pretreatment with the pan-caspase-inhibitor Z-VAD-FMK attenuated the PTE-induced apoptosis of glioma cells. Moreover, PTE significantly increased the production of reactive oxygen species (ROS) and reduce the mitochondrial membrane potential (MMP). Inhibition of ROS with N-acetyl-L-cysteine not only rescued PTE-induced reduction of cellular viability but also prevented glioma cell apoptosis. We also discovered ERK 1/2 and JNK signaling pathways were activated by PTE and contributed to induce glioma cell apoptosis. In addition, specific inhibitors of ERK 1/2 and JNK attenuated PTE-induced apoptosis. Besides, PTE significantly reduced tumor volume and prolonged median survival of tumor-bearing rats in vivo. In summary, the results of this study indicate that the anti-tumor effect of PTE on glioma cells may provide a new treatment option for glioma patients.
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Project description:Glioma is an extremely aggressive malignant neoplasm of the central nervous system. MicroRNA (miRNA) are known to bind to specific target mRNA to regulate post-transcriptional gene expression and are, therefore, currently regarded as promising biomarkers for glioma diagnosis and prognosis. The aim of the present study was to examine the pathogenesis and potential molecular markers of glioma by comparing the differential expression of miRNA and mRNA between glioma tissue and peritumor brain tissue. We explored the impact of screened core miRNA and mRNA on cell proliferation, invasion, and migration of glioma. An miRNA expression profile dataset (GSE90603) and a transcriptome profile dataset (GSE90598) were downloaded from combined miRNA-mRNA microarray chips in the Gene Expression Omnibus (GEO) database. Overall, 59 differentially expressed miRNAs (DEMs) and 419 differentially expressed genes (DEGs) were identified using the R limma software package. FunRich software was used to predict DEM target genes and miRNA-gene pairs, and Perl software was used to find overlapping genes between DEGs and DEM target genes. There were 129 overlapping genes regulated by nine miRNAs between target genes of the DEMs and DEGs. The Chinese Glioma Genome Atlas(CGGA) was analyzed in order to identify miRNAs with diagnostic and prognostic significance. MiR-139-5p, miR-137, and miR-338-3p were validated to be significantly linked to prognosis in glioma patients. Finally, we validated that miR-139-5p affected glioma malignant biological behavior via targeting gamma-aminobutyric acid A receptor alpha 1(GABRA1) through rescue experiments. Low miR-139-5p expression was correlated with survival probability and World Health Organization (WHO) grade. MiR-139-5p overexpression inhibited cell proliferation, migration, and invasion of glioma in vitro. GABRA1 was identified as a functional downstream target of miR-139-5p. Decreased GABRA1 expression was related to similar biological roles as miR-139-5p overexpression while upregulation of GABRA1 effectively reversed the inhibition effects of miR-139-5p. These results demonstrate a novel axis for miR-139-5p/GABRA1 in glioma progression and provide potential prognostic predictors and therapeutic target for glioma patients.
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Project description:Tumor necrosis factor-α-induced protein 8 (TNFAIP8) expression has been linked to tumor progression in various cancer types, but the detailed mechanisms of TNFAIP8 are not fully elucidated. Here we define the role of TNFAIP8 in early events associated with development of hepatocellular carcinoma (HCC). Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins. TNFAIP8 also exhibited binding with fatty acids and modulated expression of lipid/fatty-acid metabolizing enzymes. Chronic feeding of mice with alcohol increased hepatic levels of TNFAIP8, autophagy, and steatosis but not in high-fat-fed obese mice. Similarly, higher TNFAIP8 expression was associated with steatotic livers of human patients with a history of alcohol use but not in steatotic patients with no history of alcohol use. Our data indicate a novel role of TNFAIP8 in modulation of drug resistance, autophagy, and hepatic steatosis, all key early events in HCC progression.
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Project description:Emerging evidence has shown that microRNA (miR)‑497 serves pivotal roles in tumorigenesis, cancer progression, metastasis and chemotherapy resistance in several types of cancer. In the present study, the expression and biological functions of miR‑497 host gene (MIR497HG) were investigated in glioma tissue. The expression levels of miR‑497 and MIR497HG were measured in glioma, adjacent non‑cancerous and normal brain tissue and their association with the prognosis of patients with glioma were analyzed. The biological roles of miR‑497 and MIR497HG were investigated in glioma cell lines. In addition, bioinformatics analysis, luciferase reporter assay and functional experiments were performed to identify and validate the downstream targets of miR‑497 or MIR497HG. The expression levels of miR‑497 and MIR497HG were downregulated in glioma tissue and cell lines compared with those in adjacent non‑cancerous and normal brain tissue and normal human cortical neuron cell line. Patients with low miR‑497 or MIR497HG expression levels exhibited a poor prognostic outcome. In addition, forced overexpression of miR‑497 or MIR497HG significantly inhibited the proliferation and cell cycle progression of glioma cell lines. Furthermore, the results indicated that miR‑497 and MIR497HG exerted their biological functions by direct targeting of cyclin E1 and miR‑588/tumor suppressor candidate 1. In summary, the data indicated that miR‑497 and MIR497HG served as tumor suppressors and may be used as potential therapeutic targets and prognostic biomarkers in glioma.
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Project description:AimsMcl-1, an antiapoptotic member of the Bcl-2 family, is overexpressed in human glioblastoma, conferring a survival advantage to tumor cells. The mechanisms underlying its dysregulation have not been clarified. In this study, we explored the involvement of micro-RNAs that acted as endogenous sequence-specific suppressors of gene expression.Methods and resultsUsing computational and TCGA analysis, we identified miR-139 as being downregulated in glioblastoma in comparison with human brain tissue, as well as possessing a putative target site in Mcl-1 mRNA. Overexpression of miR-139 led to a clear decrease in Mcl-1 expression in gliomas. Reporter assays revealed direct post-transcriptional regulation involving miR-139 and the 3'-untranslated region of Mcl-1. Human glioma tissues with low expression of miR-139 displayed higher expression of Mcl-1 protein than those with high expression, suggesting that low miR-139 contributes to Mcl-1 overexpression. In addition, upregulation of miR-139 suppressed the proliferation and enhanced temozolomide (TMZ)-induced apoptosis. Finally, we observed that Mcl-1 knockdown resulted in similar effects compared with miR-139 transfection.ConclusionOur results suggested that miR-139 negatively regulated Mcl-1 and induced apoptosis in cooperation with an anticancer drug TMZ in glioma.
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Project description:Objective: Micro-RNA plays a critical role in the pathological process of gliomas. Previous research showed that the level of miR-155 was significantly increased in many cancers, including gliomas. However, the mechanism of glioma is still unknown. Method: To investigate the regulatory function of miR-155 on glioma U87-MG cells and its effects on related signaling pathways. After transfection of miR-155 mimic and inhibitor, the level of miR-155 were applied to detect cell proliferation, apoptosis, senescence index, invasive ability and cell migration at different time points (0, 24, 24 h, respectively) by CCK8 assay, flow cytometry, ?-galactosidase (?-gal) staining, transwell and scratch test, respectively. The effect of miR-155 on PI3K/AKT signal pathway was observed at meantime. Results: Compared with the control group, after miR-155 mimic transfection, U87-MG cell viability, cell migration rate and invasiveness were increased, while apoptosis and senescence were significantly decreased, which was the opposite on miR-155 inhibitor transfection. The phosphorylation levels of miR-155, PI3K, AKT, PI3K, and AKT in U87-MG cells intervened with miR-155 mimic also increased significantly, while the levels of PTEN, Caspase-3, Caspase-9 mRNA, and protein declined significantly, with statistically significant difference. Meanwhile, compared with the control group, miR-155 inhibitor group were on the contrary. Conclusion: The study indicated that miR-155 take charge a key function in regulating the proliferation, migration, and invasion of glioma U87-MG cells through PI3K/AKT signaling pathway, and has anti-glioma effects by inhibition of miR-155, which provided ideas for further clinical treatment of glioma patients.
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Project description:Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, has been considered a potential therapeutic and chemopreventive agent for cancer. Glioma is a malignant tumor with high mortality but effective therapy has not yet been developed. In this study, we found that EGCG induced apoptosis in U251 glioma cells via the laminin receptor (molecular weight 67 kDa) in a time- and dose-dependent manner, decreased their invasiveness and inhibited their proliferation. The mitogen-activated protein kinase pathway was shown to be involved in glioma cell apoptosis and proliferation. Furthermore, the mRNA levels of matrix metalloproteinase (MMP)-2 and MMP-9 were reduced after EGCG treatment. These results suggest that EGCG has important therapeutic effects with low toxicity and side-effects, and could be used in cancer chemoprevention.
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Project description:Aberrant expression of miR-374a has been reported in several types of human cancers, including lung cancer. However, the functional significance and molecular mechanisms underlying the role of miR-374a in lung cancer remain largely unknown. We found that the expression of miR-374a was significantly downregulated in lung adenocarcinoma tissues compared to adjacent normal lung tissues in samples included in The Cancer Genome Atlas. Functional studies revealed that overexpression of miR-374a led to inhibition of lung adenocarcinoma cell proliferation, migration and invasion and that miR-374a negatively regulated transforming growth factor-alpha (TGFA) gene expression by directly targeting the 3'-UTR of TGFA mRNA. Treating lung adenocarcinoma cells with TGF-α neutralizing antibody resulted in suppression of cell proliferation and invasion, which mimicked the action of miR-374a. Additionally, TGFA gene expression was significantly higher in tumor tissues compared to adjacent normal tissue and high TGFA gene expression strongly correlated with poor survival in patients with lung adenocarcinoma. Taken together, our studies suggest that miR-374a suppresses lung adenocarcinoma cell proliferation and invasion via targeting TGFA gene expression. Our findings may provide novel treatment strategies for lung adenocarcinoma patients.
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Project description:The microRNA (mir)-374a has been implicated in several types of human cancer; however, its role in diabetic nephropathy (DN) remains unclear. Monocyte chemoattractant protein (MCP)-1 is a chemokine that recruits macrophages to inflammatory sites and is important for the development and progression of DN. However, the relationship between miR-374a and MCP-1 in DN is unknown. We addressed this in the present study by examining the expression of these factors in kidney tissue samples from DN patients and through loss- and gain-of-function experiments using HK2 human renal tubular epithelial cells. We found that miR-374a was downregulated whereas MCP-1 was upregulated in DN tissue. A bioinformatics analysis revealed that MCP-1 is a putative target of miR-374a. To confirm this relationship, HK2 cells treated with normal glucose (5.6 mmol/l D-glucose), high glucose (HG) (30 mmol/l D-glucose), or high osmotic pressure solution (5.6 mmol/l D-glucose + 24.4 mmol/l D-mannitol) were transfected with miR-374a mimic or inhibitor. miR-374a mimic reduced MCP-1 mRNA expression and migration of co-cultured U937 cells, whereas miR-374a inhibition had the opposite effects. Additionally, interleukin-6 and -18 and tumor necrosis factor-α levels were downregulated by transfection of miR-374a mimic. On the other hand, MCP-1 overexpression reversed the inhibitory effects of miR-374a in HK2 cells. Thus, miR-374a suppresses the inflammatory response in DN through negative regulation of MCP-1 expression. These findings suggest that therapeutic strategies that target the miR-374a/MCP-1 axis can be an effective treatment for DN.
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