Targeting adaptive glioblastoma: an overview of proliferation and invasion.
Ontology highlight
ABSTRACT:
SUBMITTER: Xie Q
PROVIDER: S-EPMC4232088 | biostudies-literature | 2014 Dec
REPOSITORIES: biostudies-literature
Publications
Targeting adaptive glioblastoma: an overview of proliferation and invasion.
Xie Qian Q Mittal Sandeep S Berens Michael E ME
Neuro-oncology 20140730 12
Glioblastoma is one of the most devastating cancers, in which tumor cell infiltration into surrounding normal brain tissue confounds clinical management. This review describes basic and translational research into glioma proliferation and invasion, in particular the phenotypic switch underlying a stochastic "go or grow" model of tumor cell behavior. We include recent progress in system genomics, cancer stem cell theory, and tumor-microenvironment interaction, from which novel therapeutic strateg ...[more]
Similar Datasets
Project description:Glioblastoma multiforme (GBM) is the most common primary malignant tumors originating in the brain parenchyma. At present, GBM patients have a poor prognosis despite the continuous progress in therapeutic technologies including surgery, radiotherapy, photodynamic therapy, and chemotherapy. Recent studies revealed that miR-101 was remarkably down-regulated in kinds of human cancers and was associated with aggressive tumor cell proliferation and stem cell self-renewal. Data also showed that miR-101 was down-regulated in primary glioma samples and cell lines, but the underlying molecular mechanism of the deregulation of miR-101 in glioma remained largely unknown. In this study, we found that miR-101 could inhibit the proliferation and invasion of glioma cells both in vitro and in vivo by directly targeting SOX9 [sex-determining region Y (SRY)-box9 protein]. Silencing of SOX9 exerted similar effects with miR-101 overexpression on glioma cells proliferation and invasion. Quantitative reverse transcription PCR and Western blotting analysis revealed a negative relationship between miR-101 and SOX9 in human glioma U251MG and U87MG cells, and the luciferase assay indicated that miR-101 altered SOX9 expression by directly targeting on 3'UTR. Taken together, our findings suggest that miR-101 regulates glioma proliferation, migration and invasion via directly down-regulating SOX9 both in vitro and in vivo, and miR-101 may be a potential therapeutic target for future glioma treatment.
| S-EPMC5386681 | biostudies-literature
Project description:Increasing evidence has indicated that aberrant expression of miRNAs has been shown to be strongly implicated in the initiation and progression of glioblastoma. Here, we identified a novel tumor suppressive miRNA, miR-564, and investigated its role and therapeutic effect for glioblastoma. We showed that miR-564 was down-regulated in human glioblastoma tissues and cell lines. Introduction of miR-564 dramatically inhibited cell growth and invasion in glioblastoma cells. Subsequent experiments revealed that Transforming growth factor-?1 (TGF-?1) was a direct and functional target of miR-564 in glioblastoma cells. Furthermore, overexpression of miR-564 decreased p-SMAD and SMAD4 expression, which are the downstream signaling molecules of TGF-?. Meanwhile, ectopic of miR-564 reduced the messenger RNA (mRNA) and protein expression of epidermal growth factor receptor (EGFR) and MMP9. Furthermore, the upregulation of miR-564 suppressed TGF-?-mediated U87 proliferation and migration. The expression of EGFR and MMP9 was upregulated in glioblastoma tissues compared to their normal tissues. The EGFR and MMP9 expression levels were inverse correlated with the expression of miR-564. miR-564 suppressed the growth of U87-engrafted tumors. These findings reveal that miR-564/TGF-?1 signaling that may be required for glioblastoma development and may consequently serve as a new therapeutic target for the treatment of glioblastoma.
| S-EPMC5302907 | biostudies-other
Project description:Glioblastoma (GBM) is the most common type of adult primary brain tumor with a median survival rate of less than 15 months, regardless of the current standard of care. Cellular heterogeneity, self-renewal ability and tumorigenic glioma cancer stem cell (GSC) populations contribute to the difficulty in treating GBM. G-protein-coupled receptors (GPCRs) are the largest group of membrane proteins and mediate many cellular responses. Regulators of G-protein signaling 4 (RGS4) are negative regulators of G-protein signaling, and elevated levels of RGS4 are reportedly linked with several human diseases, including cancer. This study investigates the effect of silencing RGS4, resulting in inhibition of GSC growth, invasion and migration. Data obtained from The Cancer Genome Atlas (TCGA) demonstrated poor patient survival with high expression of RGS4. Immunohistochemistry and immunoblot analysis conducted on GBM patient biopsy specimens demonstrated increased RGS4 expression correlative with the TCGA data. RNA sequencing confirmed a significant decrease in the expression of markers involved in GSC invasion and migration, particularly matrix metalloproteinase-2 (MMP2) in knockout of RGS4 using CRISPR plasmid (ko-RGS4)-treated samples compared to parental controls. Gelatin zymography confirmed the reduced activity of MMP2 in ko-RGS4-treated samples. Silencing RGS4 further reduced the invasive and migratory abilities and induction of apoptosis of GSCs as evidenced by Matrigel plug assay, wound healing assay and human apoptosis array. Collectively, our results showed that the silencing of RGS4 plays an important role in regulating multiple cellular functions, and is an important therapeutic target in GBM.
| S-EPMC7247588 | biostudies-literature
Project description:BackgroundIncreasing evidence has indicated that microRNAs (miRNAs) are strongly implicated in the initiation and progression of glioblastoma multiforme (GBM). Here, we identified a novel tumor suppressive miRNA, miR-377, and investigated its role and therapeutic effect for GBM.MethodsMiRNA global screening was performed on GBM patient samples and adjacent nontumor brain tissues. The expression of miR-377 was detected by real-time reverse-transcription PCR. The effects of miR-377 on GBM cell proliferation, cell cycle progression, invasion, and orthotopic tumorigenicity were investigated The therapeutic effect of miR-377 mimic was explored in a subcutaneous GBM model. Western blot and luciferase reporter assay were used to identify the direct and functional target of miR-377.ResultsMiR-377 was markedly downregulated in human GBM tissues and cell lines. Overexpression of miR-377 dramatically inhibited cell growth both in culture and in orthotopic xenograft tumor models, blocked G1/S transition, and suppressed cell invasion in GBM cells. Importantly, introduction of miR-377 could strongly inhibit tumor growth in a subcutaneous GBM model. Subsequent investigation revealed that specificity protein 1 (Sp1) was a direct and functional target of miR-377 in GBM cells. Silencing of Sp1 recapitulated the antiproliferative and anti-invasive effects of miR-377, whereas restoring the Sp1 expression antagonized the tumor-suppressive function of miR-377. Finally, analysis of miR-377 and Sp1 levels in human GBM tissues revealed that miR-377 is inversely correlated with Sp1 expression.ConclusionThese findings reveal that miR-377/Sp1 signaling that may be required for GBM development and may consequently serve as a therapeutic target for the treatment of GBM.
| S-EPMC4201073 | biostudies-literature
Project description:Glioblastoma Multiforme (GBM) is the most common and aggressive human brain tumor, associated with very poor survival despite surgery, radiotherapy and chemotherapy.The epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor β (PDGFRβ) are hallmarks in GBM with driving roles in tumor progression. In approximately half of the tumors with amplified EGFR, the EGFRvIII truncated extracellular mutant is detected. EGFRvIII does not bind ligands, is highly oncogenic and its expression confers resistance to EGFR tyrosine kinase inhibitors (TKIs). It has been demonstrated that EGFRvIII-dependent cancers may escape targeted therapy by developing dependence on PDGFRβ signaling, thus providing a strong rationale for combination therapy aimed at blocking both EGFRvIII and PDGFRβsignaling.We have recently generated two nuclease resistant RNA aptamers, CL4 and Gint4.T, as high affinity ligands and inhibitors of the human wild-type EGFR (EGFRwt) and PDGFRβ, respectively.Herein, by different approaches, we demonstrate that CL4 aptamer binds to the EGFRvIII mutant even though it lacks most of the extracellular domain. As a consequence of binding, the aptamer inhibits EGFRvIII autophosphorylation and downstream signaling pathways, thus affecting migration, invasion and proliferation of EGFRvIII-expressing GBM cell lines.Further, we show that targeting EGFRvIII by CL4, as well as by EGFR-TKIs, erlotinib and gefitinib, causes upregulation of PDGFRβ. Importantly, CL4 and gefitinib cooperate with the anti-PDGFRβ Gint4.T aptamer in inhibiting cell proliferation.The proposed aptamer-based strategy could have impact on targeted molecular cancer therapies and may result in progresses against GBMs.
| S-EPMC4741949 | biostudies-literature
Project description:Glioblastoma is one of the most common malignant primary tumors and develops in brain. The molecular mechanism that regulates glioblastoma occurrence still remains unknown. MicroRNA (miR)?500a?5p has been reported to be involved in hepatocellular carcinoma and breast cancer. Whether miR?500a?5p regulates glioblastoma progression requires further investigation. In the present study, miR?500a?5p was highly expressed in malignant glioblastoma tissues and cell lines. Overexpression of miR?500a?5p promoted glioblastoma cell proliferation, migration and invasion in vitro. In addition, knockdown of miR?500a?5p accelerated cell apoptosis. Furthermore, miR?500a?5p inhibition significantly impaired tumor growth in vivo. The present study further explored the downstream mechanism. The luciferase reporter assay revealed that miR?500a?5p directly binds the 3'?untranslated region of chromodomain helicase DNA binding protein 5 (CHD5) mRNA. MiR?500a?5p markedly inhibited CHD5 expression in glioblastoma cells. Furthermore, CHD5 was downregulated in glioblastoma tissues, and the expression levels of miR?500a?5p and CHD5 were inversely correlated. In addition, knockdown of CHD5 restored the inhibition of cell proliferation and migration triggered by miR?500a?5p silence. Finally, it was demonstrated that miR?500a?5p can serve as a novel biomarker for the diagnosis and prognosis of glioblastoma patients. Taken together, the results of the present study indicated that miR?500a?5p may have promoted glioblastoma development and progression by targeting CHD5.
| S-EPMC6102694 | biostudies-literature
Project description:Glioblastoma (GBM) is a type of malignant tumor occurring in the brain that severely influences the life of affected individuals. GBM cells are highly infiltrative, which is one of the main obstacles in the treatment of the disease. Numerous microRNAs (miRNAs/miRs) are associated with the development of GBM. However, the effects of miR-15a-5p on GBM remain elusive. In the present study, reverse transcription-quantitative PCR and western blot analysis were applied for the detection of RNA and protein levels, respectively. Cell Counting Kit-8 and Transwell assays were performed to examine cell proliferation and invasion, respectively. TargetScan 7.1 and dual-luciferase reporter assay were utilized for the prediction and verification of the association between miRNAs and mRNAs. The present study revealed that miR-15a-5p expression was upregulated in the GBM T98G cell line. The results further demonstrated that, through the inhibition of cell adhesion molecule 1 expression and the promotion of Akt phosphorylation, miR-15a-5p was able to promote GBM cell proliferation and invasion. Overall, the present findings revealed a novel mechanism responsible for the development of GBM and provided an experimental basis for the diagnosis and treatment of GBM.
| S-EPMC7751353 | biostudies-literature
Project description:Grade IV astrocytoma, also known as glioblastoma multiforme (GBM), is the most common and aggressive intracranial glial tumor. GBM is associated with very poor survival and effective treatments have remained elusive so far. Mounting evidence indicates that CD164 contributes to stemness and tumorigenesis in normal cells and is overexpressed in various tumor types, including glioblastoma. Using tissue microarray immunohistochemistry, we show that there is a significant correlation between CD164 expression and glioma type and grade. Depletion of CD164 expression in human glioblastoma cells with siRNA reduced proliferation, migration, and invasiveness. In parallel, immunoblotting showed that downregulation of CD164 expression decreased Akt activation and modified the expression of autophagy markers by upregulating Beclin-1 and LC3B and downregulating p62. These effects were mimicked by inhibition of Akt with MK2206, which suggests that CD164 induces autophagy via Akt/Beclin-1 signaling. We propose that CD164 may serve as a GBM molecular marker and a potential target in therapeutic strategies aimed to improve outcomes for this devastating brain tumor.
| S-EPMC6459350 | biostudies-literature
Project description:Accumulating evidence has implicated the deregluation of miRNAs in tumorigenesis. Previous studies have reported that microRNA-195 (miR-195) is markedly down-regulated in human glioblastoma cells, compared with normal brain tissue, but the biological role of miR-195 in glioblastoma development is currently unknown. In this study, we define a tumor-suppressor role for miR-195 in human glioblastoma cells. Over-expression of miR-195 in glioblastoma cell lines robustly arrested cell cycle progression and significantly repressed cellular invasion. We identified E2F3 and CCND3 as functional downstream targets of miR-195 in glioblastoma cells. Through knockdown studies, we demonstrated that E2F3 was the dominant effector of miR-195-mediated cell cycle arrest and that CCND3 was a key mediator of miR-195-induced inhibition of glioblastoma cell invasion. Furthermore, we showed that p27(Kip1) was an important regulator downstream of CCND3 and that the accumulation of p27(Kip1) in the cytoplasm might be responsible for the miR-195-mediated cell invasion inhibition in glioblastoma cells. This work provides evidence for the initial mechanism by which miR-195 negatively regulates both the proliferation and invasion of glioblastoma cells, suggesting that the down-regulation of miR-195 might contribute to the malignant transformation of glioblastoma cells and could be a molecular signature associated with glioblastoma progression.
| S-EPMC3280801 | biostudies-other
Project description:Introduction:Glioblastomas (GBM) are the most frequent and aggressive human brain tumors due to their high capacity to migrate, invade healthy brain tissue, and resist anticancer therapies. It has been reported that testosterone (T) levels are higher in patients with GBM than in healthy controls. It has also been dem{}onstrated that T induces proliferation, migration, and invasion of human GBM cell lines. T is mainly metabolized to 5?-dihydrotestosterone (DHT) by the enzyme 5?-reductase (5?R), but the role of this metabolite in GBM cells is unknown. Methods:The expression of 5?R isoenzymes and AR in biopsies of GBMs was determined by the analysis of TCGA. U87 and U251 GBM cell lines were grown in supplemented DMEM. For evaluating the expression of AR in U251 and U87 cells, a RT-qPCR was performed. The cells were treated with T, DHT, finasteride (FIN), dutasteride (D), and the combined treatments, FIN+T and D+T or vehicle. After treatments, the viability was quantified by the trypan blue exclusion assay, the proliferation was evaluated by BrdU incorporation, and migration and invasion were analyzed by the scratch-wound and the transwell assays, respectively. Results:In a set of glioma biopsies from TCGA, we observed that SRD5A2 (5?R2) expression was higher in GBM and in low-grade gliomas than in normal brain tissue. We observed that DHT and T increased proliferation, migration, and invasion of human GBM cell lines: U87 and U251. F and D, drugs that inhibit 5?R activity, blocked the effects of T on GBM cells. Discussion:These data suggest that T induces human GBM progression through its conversion into DHT. These results can be related to the chemical structure of DHT, which increases its affinity for AR and decreases five times the rate of dissociation compared to T. Also, it is possible that DHT mediates the effects of T on cell human GBM cells motility by changing the expression of genes involved in tumor infiltration.
| S-EPMC7490433 | biostudies-literature