Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant gliomas are highly invasive tumors with an almost invariably rapid and lethal outcome. Surgery and chemoradiotherapy fail to remove resistant tumor cells that disperse within normal tissue, which are a major cause for disease progression and therapy failure. Infiltration of the neural parenchyma is a distinctive property of malignant gliomas compared with other solid tumors. Thus, glioma cells are thought to produce unique molecular changes that remodel the neural extracellular matrix and form a microenvironment permissive for their motility. Here, we describe the unique expression and proinvasive role of fibulin-3, a mesenchymal matrix protein specifically upregulated in gliomas. Fibulin-3 is downregulated in peripheral tumors and is thought to inhibit tumor growth. However, we found fibulin-3 highly upregulated in gliomas and cultured glioma cells, although the protein was undetectable in normal brain or cultured astrocytes. Overexpression and knockdown experiments revealed that fibulin-3 did not seem to affect glioma cell morphology or proliferation, but enhanced substrate-specific cell adhesion and promoted cell motility and dispersion in organotypic cultures. Moreover, orthotopic implantation of fibulin-3-overexpressing glioma cells resulted in diffuse tumors with increased volume and rostrocaudal extension compared with controls. Tumors and cultured cells overexpressing fibulin-3 also showed elevated expression and activity of matrix metalloproteases, such as MMP-2/MMP-9 and ADAMTS-5. Taken together, our results suggest that fibulin-3 has a unique expression and protumoral role in gliomas, and could be a potential target against tumor progression. Strategies against this glioma-specific matrix component could disrupt invasive mechanisms and restrict the dissemination of these tumors.
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PMID:Fibulin-3 is uniquely upregulated in malignant gliomas and promotes tumor cell motility and invasion. 1988 59

Cyclooxygenase-2 (COX-2) and Protein kinase B (PKB/Akt) play a crucial role in the formation of many malignant tumors and have been shown to be the important therapeutic targets. In the present study, we examined immunohistochemical expression of phosphorylated Akt (p-Akt) and COX-2 in 45 gastric adenocarcinomas with different tumor grades. Then, adenovirus-mediated small hairpin RNA (shRNA) expression vectors rAd5-Akt1+COX-2 (rAd5-A+C) that target sequences of human COX-2 and Akt1 were used to examine the inhibitory effects on cell proliferation, invasion and apoptosis in SGC7901 gastric adenocarcinoma and U251 glioma cells. Cell growth was inhibited by over 70%, as indicated by a MTT assay, and was accompanied by G1/G0 phase arrest in the rAd5-A+C treated group, indicating poor cell growth activities. The number of cells invading through the matrigel in the rAd5-A+C treated group was significantly decreased (36.2+/-3.1) compared with that of the control group SGC7901 (105.0+/-4.0) and the nonsense sequence group rAd5-HK (102.5+/-6.4). In addition, the tumor volumes in the SGC7901 subcutaneous nude mouse model treated with rAd5-A+C was significantly smaller than those of the control group and nonsense sequence group rAd5-HK. When COX-2 and Akt1 were dramatically downregulated, Ki-67, CyclinD1, MMP-2, MMP-9 and Bcl-2 were also downregulated. Our results demonstrated that p-Akt and COX-2 were overexpressed in gastric adenocarcinomas and their expression levels were elevated with the ascending order of tumor malignancy; rAd5-A+C targeting COX-2 and Akt1 downregulated their expression significantly in a sequence-specific manner, exerting inhibitory effects on SGC7901 and U251 cell proliferation, invasion and apoptosis. In conclusion, our data suggest a novel mechanism for the regulation of malignant tumor cell growth and provide evidence for combined gene therapy for malignant tumors.
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PMID:Expression of p-Akt and COX-2 in gastric adenocarcinomas and adenovirus mediated Akt1 and COX-2 ShRNA suppresses SGC-7901 gastric adenocarcinoma and U251 glioma cell growth in vitro and in vivo. 1992 30

Malignant gliomas including glioblastoma multiforme (GBM) and anaplastic astrocytomas are the most common primary brain tumors. Despite multimodal treatment including surgery, chemotherapy, and radiation, median survival for patients with GBMs is only 12 to 15 months. Identifying molecules critical for glioma progression is crucial for devising effective targeted therapy. In the present study, we investigated the potential contribution of astrocyte elevated gene-1 (AEG-1) in gliomagenesis and explored the possibility of AEG-1 as a therapeutic target for malignant glioma. We analyzed the expression levels of AEG-1 in 9 normal brain tissues and 98 brain tumor patient samples by Western blot analysis and immunohistochemistry. AEG-1 expression was significantly elevated in >90% of diverse human brain tumor samples including GBMs and astrocytic tumors, and also in human glioma cell lines compared with normal brain tissues and normal astrocytes. Knockdown of AEG-1 by small interfering RNA inhibited cell viability, cloning efficiency, and invasive ability of U87 human glioma cells and 9L rat gliosarcoma cells. We also found that matrix metalloproteases (MMP-2 and MMP-9) are involved in AEG-1-mediated invasion of glioma cells. In an orthotopic nude mouse brain tumor model using primary human GBM12 tumor cells, AEG-1 small interfering RNA significantly suppressed glioma cell growth in vivo. Taken together, these provocative results indicate that AEG-1 may play a crucial role in the pathogenesis of glioma and that AEG-1 could represent a viable potential target for malignant glioma therapy.
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PMID:Astrocyte elevated gene-1: a novel target for human glioma therapy. 2005 77

RECK is an anti-tumoral gene whose activity has been associated with its inhibitory effects regulating MMP-2, MMP-9, and MT1-MMP. RECK level decreases as gliobastoma progresses, varying from less invasive grade II gliomas to very invasive human glioblastoma multiforme (GBM). Since RECK expression and glioma invasiveness show an inverse correlation, the aim of the present study is to investigate whether RECK expression would inhibit glioma invasive behavior. We conducted this study to explore forced RECK expression in the highly invasive T98G human GBM cell line. Expression levels as well as protein levels of RECK, MMP-2, MMP-9, and MT1-MMP were assessed by qPCR and immunoblotting in T98G/RECK+ cells. The invasion and migration capacity of RECK+ cells was inhibited in transwell and wound assays. Dramatic cytoskeleton modifications were observed in the T98G/RECK+ cells, when compared to control cells, such as the abundance of stress fibers (contractile actin-myosin II bundles) and alteration of lamellipodia. T98G/RECK+ cells also displayed phosphorylated focal adhesion kinase (P-FAK) in mature focal adhesions associated with stress fibers; whereas P-FAK in control cells was mostly associated with immature focal complexes. Interestingly, the RECK protein was predominantly localized at the leading edge of migrating cells, associated with membrane ruffles. Unexpectedly, introduced expression of RECK effectively inhibited the invasive process through rearrangement of actin filaments, promoting a decrease in migratory ability. This work has associated RECK tumor-suppressing activity with the inhibition of motility and invasion in this GBM model, which are two glioma characteristics responsible for the inefficiency of current available treatments.
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PMID:RECK-mediated inhibition of glioma migration and invasion. 2012 10

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a pivotal role in invasion and angiogenesis of malignant glioma cells. Therefore, the inhibition of MMPs has been suggested to be a promising therapeutic strategy for brain tumors. In the present study, we found that glycitein, a bacterial metabolite of the isoflavone glycitin, inhibits the expression of MMP-3 and MMP-9 at promoter, mRNA, and protein levels in PMA-stimulated U87MG human astroglioma cells. In addition, gelatin zymography showed that glycitein inhibited the PMA-induced MMP-9 secretion in U87MG cells. A subsequent Matrigel invasion assay revealed that glycitein suppresses the in vitro invasiveness of glioma cells, which may be at least partly due to the glycitein-mediated inhibition of MMP-3 and MMP-9. In support of this, treatment of MMP-3- or MMP-9-specific inhibitor significantly suppressed PMA-induced invasion of glioma cells. Further mechanistic studies revealed that glycitein inhibits the DNA binding and transcriptional activities of NF-kappaB and AP-1, which are important transcription factors for MMP-3 or MMP-9 gene expression. Furthermore, glycitein suppresses PMA-induced phosphorylation of three types of MAP kinases, which are upstream signaling molecules in MMP gene expressions and NF-kappaB and AP-1 activities in glioma cells. Therefore, the inhibition of MMP-3 and MMP-9 expression by glycitein may have therapeutic potential for controlling invasiveness of malignant gliomas.
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PMID:Glycitein inhibits glioma cell invasion through down-regulation of MMP-3 and MMP-9 gene expression. 2018 14

An increase in MMP-9 gene expression and enzyme activity with stimulating the migration of GBM8401 glioma cells via wound healing assay by 12-O-tetradecanoylphorbol-13-acetate (TPA) was detected in glioblastoma cells GBM8401. TPA-induced translocation of protein kinase C (PKC)alpha from the cytosol to membranes, and migration of GBM8401 elicited by TPA was suppressed by adding the PKCalpha inhibitors, GF109203X and H7. Activation of extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) by TPA was identified, and TPA-induced migration and MMP-9 activity was significantly blocked by ERK inhibitor PD98059 and U0126, but not JNK inhibitor SP600125. Activation of NF-kappaB protein p65 nuclear translocation and IkappaBalpha protein phosphorylation with increased NF-kappaB-directed luciferase activity by TPA were observed, and these were blocked by the PD98059 and IkB inhibitor BAY117082 accompanied by reducing migration and MMP-9 activity induced by TPA in GBM8401 cells. Transfection of GBM8401 cells with PKCalpha siRNA specifically reduced PKCalpha protein expression with blocking TPA-induced MMP-9 activation and migration. Additionally, suppression of TPA-induced PKCalpha/ERK/NK-kappaB activation, migration, and MMP-9 activation by flavonoids including kaempferol (Kae; 3,5,7,4'-tetrahydroxyflavone), luteolin (Lut; 5,7,3'4'-tetrahydroxyflavone), and wogonin (Wog; 5,7-dihydroxy-8-methoxyflavone) was demonstrated, and structure-activity relationship (SAR) studies showed that hydroxyl (OH) groups at C4' and C8 are critical for flavonoids' action against MMP-9 enzyme activation and migration/invasion of glioblastoma cells elicited by TPA. Application of flavonoids to prevent the migration/invasion of glioblastoma cells through blocking PKCalpha/ERK/NF-kappaB activation is first demonstrated herein.
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PMID:12-O-tetradecanoylphorbol-13-acetate-induced invasion/migration of glioblastoma cells through activating PKCalpha/ERK/NF-kappaB-dependent MMP-9 expression. 2045 47

Osteopontin (OPN) is widely overexpressed in various cancers, including gliomas, and plays an important role in tumorigenesis. However, the expression pattern and functions of OPN splice variants expressed in gliomas remain unclear. The aims of our current study were to examine the expression pattern and functions of OPN splice variants in gliomas. In present study, the mRNA levels of OPN splice variants are markedly increased in gliomas tissues, and all OPN splice variants were also found in U251 and U87 cells. Furthermore, knock-down and regain of function experiments were designed to explore the functions of OPN splice variants in U251 and U87 cells. Lentiviral vectors of OPN small interference RNA (siRNA) targeting all three endogenous mRNAs of OPN and OPN splice variants synonymous mutant that were not silenced by OPN siRNA were constructed. Our results showed that all OPN splice variants synonymous mutant-protected glioma cells from apoptosis induced by OPN siRNA through alteration of the levels of Bcl-2 family proteins and OPN-b Mu elicted a significant effect. Both OPN-a Mu and -c Mu promoted glioma cell invasion through alteration of the levels of uPA, MMP-2, and MMP-9 expressions and the activities of MMP-2 and MMP-9 via activation PI-3K/AKT/NF-kappaB signaling pathway. Moreover, OPN-c Mu showed the strongest effect on glioma cell invasion, while OPN-b Mu showed no effect on the invasion of U251 and U87 cells. Thus, different splice variants of OPN have divergent functions in regulating apoptosis and invasion of glioma cells, which broadens their importance in glioma biotherapy.
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PMID:Expression pattern of osteopontin splice variants and its functions on cell apoptosis and invasion in glioma cells. 2051 Nov 84

The objective of current treatment strategies for glioblastoma (GBM) is cytoreduction. Unfortunately, the deleterious migratory and invasive behavior of glial tumors remains largely unattended. The transcription factor signal transducer and activator of transcription (STAT) 3 is known to be involved in the development and progression of many different tumor types, including malignant gliomas. Beside other biological effects, STAT3 controls cell proliferation and tissue remodeling, processes common to both wound healing and tumor dissemination. Here, we report on impeded migratory and invasive potential of five different glioblastoma cell lines after treatment with AG490, a pharmacological inhibitor of the upstream STAT3 activator Janus kinase (JAK) 2. STAT3 was constitutively activated in all the cell lines tested, and treatment with AG490 eliminated the biologically active, tyrosine705-phosphorylated form of STAT3 in a dose-dependent fashion, as determined by Western blot analysis. Inhibition of activated STAT3 was paralleled by a decrease in transcriptional expression of the STAT3 target genes MMP-2 and MMP-9, and led to reduced proteolytic activity, as determined by zymography. Accordingly, the migratory behavior of all five GBM cell lines was impeded in monolayer wound-healing assays; invasive capacity in matrigel-coated trans-well assays was also hampered by treatment with AG490. The proliferative activity of the cell lines was also significantly reduced after treatment with AG490. The effects elicited by STAT3 inhibition were observed in both PTEN-expressing and PTEN-deficient cells. Because pharmacological inhibition of the JAK-2/STAT3 signaling pathway affects not only tumor cell proliferation but also the characteristic features of malignant gliomas, i.e. migration and invasion pertinent to invariable tumor recurrence and high morbidity, our findings support the idea that STAT3 is a suitable target in the treatment of brain tumors.
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PMID:Inhibition of the JAK-2/STAT3 signaling pathway impedes the migratory and invasive potential of human glioblastoma cells. 2058 25

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional and/or translational level by binding loosely complimentary sequences in the 3'untranslated regions (UTRs) of target mRNAs. Increased expressions of several miRNAs, specifically hsa-miR-21, have been reported to modulate glioma development. Here we report downregulation of miR-451 in A172, LN229 and U251 human glioblastoma cells. Increased expression of miR-451 by administration of miR-451 mimics oligonucleotides reversed the biology of each of the three cell lines, inhibiting cell growth, inducing G0/G1 phase arrest and increasing cell apoptosis. Further, treatment with miR-451 mimics oligonucleotides diminished the invasive capacity of these cells, as the number of cells invading through matrigel was significantly decreased. Akt1, CyclinD1, MMP-2, MMP-9 and Bcl-2 protein expression decreased, and p27 expression increased in a dose-dependent manner with miR-451 mimics oligonucleotides. Taken together, these studies reveal miR-451 impacts glioblastoma cell proliferation, invasion and apoptosis, perhaps via regulation of the PI3K/AKT signaling pathway. We propose an essential role for miR-451 as a tumor-suppressor of human glioma.
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PMID:MiRNA-451 plays a role as tumor suppressor in human glioma cells. 2081 46

We have previously reported the presence of Dlxin-1, a member of the melanoma antigen gene (MAGE) family, in the brain and showed its function as a cell cycle arrest protein, suggesting that Dlxin-1 may have anti-proliferative functions in rapidly growing tumors. Using the cancer stem cell hypothesis, which attributes the initiation and progression of brain tumors to the cancer-initiating stem cells, we have investigated the role of Dlxin-1 in the glioma stem cells propagated by us as a cell culture system comprising of HNGC-2 cells. Our studies provide evidence about the role of Dlxin-1 as an anti-tumorigenic protein in the highly chemo-resistant glioma stem cells. Next, we show that these anti-proliferative effects are manifested by Dlxin-1 through down regulation of the activities of MMP-2 and MMP-9, and through interaction of Dlxin-1 with its target protein P311 that is involved in glioma cell invasion. In summary, we establish the roles for Dlxin-1, one as an anti-tumorigenic and anti-invasive protein in high-grade gliomas and the other as an inducer of differentiation of glioma stem cells. These two attributes, in conjunction, result in conversion of the drug-resistant brain tumor stem cells to the tumor-attenuated cells that may now be more amenable to effective therapeutic targeting.
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PMID:Dlxin-1, a member of MAGE family, inhibits cell proliferation, invasion and tumorigenicity of glioma stem cells. 2110 81


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