Glioblastoma multiforme (GBM) is the most malignant and common brain tumor; it is aggressive growth pattern means that GBM patients face a poor prognosis even when receiving the best available treatment modalities. In recent years, an increasing number of reports suggest that the discovery of microRNAs (miRNAs) might provide a novel therapeutic target for human cancers, including GBM. One miRNA in particular, microRNA-25 (miR-25), is overexpressed in several cancers, wherein accumulating evidence indicates that it functions as an oncogene. However, the function of miR-25 in GBM has not been totally elucidated. In this study, we demonstrated that miR-25 was significantly up-regulated in astrocytoma tissues and glioblastoma cell lines. In vitro studies further demonstrated that overexpressed miR-25 was able to promote, while its antisense oligos inhibited cell proliferation and invasion in U251 cells. Moreover, we identified neurofilament light polypeptide (NEFL) as a novel target molecule of miR-25. Also of note was the fact that NEFL was down-regulated with increased levels of miR-25 expression in human astrocytoma clinical specimens. In addition, via the mTOR signaling pathway, NEFL-siRNA could significantly attenuate the inhibitory effects of knockdown miR-25 on the proliferation and invasion of U251 cells. Overall, our results showed an important role for miR-25 in regulating NEFL expression in GBM, and suggest that miR-25 could be a potential target for GBM treatment.
MicroRNAs (miRs) serve important roles in glioma. However, the underlying molecular mechanism of miR-25 in glioma progression remains largely unknown; therefore, it was investigated in the present study. RT-qPCR analysis revealed that miR-25 expression levels were markedly increased in human glioma tissue and glioma cell lines compared with normal brain tissues and normal human astrocytes, respectively. miR-25 upregulation exhibited an association with glioma progression, and the knockdown of miR-25 significantly inhibited glioma cell proliferation and migration. F-box and WD repeat domain containing 7 (FBXW7) and dickkopf WNT signaling pathway inhibitor 3 (DKK3) were identified as target genes of miR-25. FBXW7 and DKK3 expression levels were significantly downregulated in glioma tissue samples compared with normal brain tissue, and their expression levels were negatively regulated by miR-25 expression in glioma cells. Furthermore, inhibition of FBXW7 and DKK3 expression suppressed the miR-25-induced effects on glioma cell proliferation and migration. The findings of the present study suggest that miR-25 may promote glioma cell proliferation and migration by inhibiting the expression of FBXW7 and DKK3. Therefore, miR-25 may serve as a promising molecular target for the treatment of glioma.
Glioma is the most common primary brain tumor in adults. Six3 is a human homologue of the highly conserved sine oculis gene family and essential transcription regulatory factor in process of eye and fetal forebrain development. However, little is known about the role of Six3 in human tumorigenesis. The aim of this study is to investigate the methylation/expression of Six3 and reveal its function and action mechanism in glioma. Our results showed that Six3 was down-regulated in human glioma tissues and human glioma SHG-44, U251, SF126 and U373-MG cells compared with the normal tissues. And the down-regulation of Six3 was associated with the methylation of its promoter. Glioma U251 cells lacked endogenous Six3. Treatment with demethylating agent (5-aza-2'-deoxycytidine) or exogenous expression of Six3 restored Six3 production and resulted in suppression of cell cycle G1/S transition, proliferation and invasion and down-regulation of the expression of Wnt1, p-GSK3-β, β-catenin and cyclin D1 in glioma U251 cells. However, knockdown of Six3 in SHG-44 cells, which have relative higher baseline level of Six3, resulted in an opposite action. These results demonstrate that Six3 silence or loss in glioma is induced by its promoter hypermethylation and Six3 down-regulation contributes to proliferation and invasion of glioma. And this process is involved in activation of Wnt/β-catenin pathway. Six3 play a suppressor role in the initiation and progression of human glioma and potentially serve as a target for the diagnosis and treatment of human glioma.
Glioblastoma multiforme (GBM), the most common primary brain cancer in adults, is usually the most lethal type of brain tumor. MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules that deeply involves with the regulation of gene expression and cellular processes, including proliferation, apoptosis, migration and invasion. The objective of the study is to investigate the effect of miRNA-429 on human glioblastoma tissues and cell lines. miRNA-429 expressions in human glioblastoma, normal brain tissue samples, and human malignant glioma cell lines (U87, U251 and LN229) were compared using reverse transcription-quantitative PCR and western blot methods. U251 cell lines were transfected with miRNA-429 mimics, and then the effects of miRNA-429 on cell proliferation and invasion were investigated by CCK8 and Transwell invasion assay, respectively. It was found that miRNA-429 expression was significantly reduced in the examined Glioblastoma samples and human glioma cell lines. Overexpression of miRNA-429 inhibited Glioblastoma cell proliferation and invasion. Additionally, the present study also showed that BMI1 was a functional target of miRNA-429. Overexpression of BMI1 undermined the inhibition effect of miRNA-429 in glioblastoma and U251 cell lines. The current study demonstrated that miRNA-429, as a tumor suppressor gene, was capable of negatively regulating the expression of BMI1 in U251 cells.
The endothelin (ET) axis has been implicated in astrocytoma growth and progression. Selective ETB receptor antagonists blocked proliferation and induced apoptosis in astrocytoma cell lines, suggesting that the ETB receptor could be a therapeutic target for astrocytomas. In the present study, we explored the association of the ETB receptor expression with clinicopathological variables and the prognosis of human astrocytomas, by examining the ETB receptor expression and Ki-67 staining in 71 surgically resected astrocytomas with immunohistochemistry. High expression of the ETB receptor was significantly associated with high grade of astrocytomas (p < .0001) and high Ki-67 labeling index (LI; p < .0001). Kaplan-Meier survival analysis showed that the ETB receptor high expression group had significantly shorter disease-free survival (DFS) and overall survival (OS) rates than the low expression group (p < .001). Multivariate analysis with the Cox's proportional hazards model revealed that high expression of the ETB receptor, high WHO grade, and high Ki-67 LI were independent factors for shorter DFS and OS (p < .05 for each comparison). In conclusion, high expression of the ETB receptor is closely associated with high malignancy and poor prognosis of human astrocytomas, which suggests that the ETB receptor could be a promising therapeutic target for astrocytomas, particularly high-grade astrocytomas.
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