Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Comparison of gene expressing profiles between gliomas with different grades revealed frequent overexpression of insulin-like growth factor binding protein 2 (IGFBP2) in glioblastoma (GBM), the most advanced stage of glioma. To determine whether IGFBP2 is involved in the proliferative and invasive nature of GBM, we established stable SNB19 GBM cell lines that overexpress IGFBP2. Although there was no marked difference in the cell growth between IGFBP2 overexpressing SNB19(BP2) lines when compared with the control cells, these clones showed significantly increased invasive rates when compared with the parental or vector transfected SNB19 cells. Total RNAs from controls and SNB19(BP2) clones were used for microarray analysis to detect IGFBP2-mediated alterations in gene expression. When compared with parental or vector-transfected control cells, SNB19(BP2) cells consistently showed 3-5-fold increase in the expression of matrix metalloproteinase-2 (MMP-2) as well as other invasion related genes. Increased MMP-2 expression in SNB19(BP2) cells was subsequently confirmed by real time reverse-transcription PCR, Western blotting, and gelatin zymography. Furthermore, consistent with increased MMP-2 expression in SNB19(BP2) cells, transient transfection of a MMP-2 promoter/luciferase reporter also resulted in 3-6-fold higher luciferase activity in SNB19(BP2) cells than in parental or vector-transfected control cells. Finally, tissue microarray analysis of 68 GBM tissue specimens showed a significant correlation between the overexpression of IGFBP2 and elevated MMP-2 expression. Taken together, our data provide evidence that IGFBP2 contributes to glioma progression in part by enhancing MMP-2 gene transcription and in turn tumor cell invasion.
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PMID:Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. 1290 97

Glucose transporter-1 (GLUT1) mediates uptake of glucose and is up-regulated in some cancers. The amount of this membrane protein is regulated by a post-transcriptional mechanism in which mRNA binding proteins recognize cis-acting elements in the 3'-untranslated (3'UTR) of the mRNA. To identify cis elements in GLUT1 mRNA we introduced 3'UTR sequences into the 3'UTR of the luciferase gene in a reporter construct. A 30 nt adenosine-uridine-rich element ("GLUT1 AURE") inhibited luciferase activity in HEK-293 cells. This inhibitory effect was confirmed by deleting the GLUT1 AURE from a reporter containing the full-length 3'UTR. Deletion of the GLUT1 AURE caused reporter activity to increase. Deletion of a larger fragment ("Bsu" region) containing the GLUT1 AURE increased reporter activity still further, suggesting that there are additional cis elements in the GLUT1 mRNA. The GLUT1 AURE was also active in GBM-T98G glioblastoma cells. Next, we tested the action of a trans-acting factor, hnRNP A2, on GLUT1 gene expression. We show that a cytoplasmic-localizing isoform of hnRNP A2 binds human GLUT1 RNA by gel-shift assay and by UV-crosslinking. Finally, over-expression of the hnRNP A2 isoform inhibited GLUT1 reporter expression in GBM-T98G cells. These results identify the AURE cis element in human GLUT1 mRNA and show that hnRNP A2 acts on GLUT1 mRNA to inhibit expression of GLUT1 in a brain cancer cell line.
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PMID:Post-transcriptional regulation of glucose transporter-1 by an AU-rich element in the 3'UTR and by hnRNP A2. 1514 68

Gene therapy has the potential to become an effective component of cancer treatment by transferring genes that cause immunomodulation or tumor cell death or that inhibit angiogenesis into tumor cells or tumor-associated stroma. Viral vectors have been the primary gene transfer vehicles used for intratumoral gene transfer to date. Plasmid-based vectors may be safer and more scalable than viral vectors. However, attempts at plasmid-based intratumoral gene transfer have been met with transient expression and poor gene transfer efficiency. Here we report integration and long-term expression of reporter genes in human glial tumors, growing in nude mice, using the Sleeping Beauty (SB) transposon system. A two-plasmid system was used, in which linear polyethylenimine was complexed with a GFP, NEO, or luciferase transposon plasmid and a SB transposase-expressing plasmid. SB-mediated transposition led to chromosomal integration of the NEO transgene in roughly 8% of tumor cells. SB-mediated insertions were cloned from the genomes of glial tumor cells to provide molecular proof of transposase-mediated integration. Luciferase studies showed that SB facilitated long-term expression of the transgene in glial tumors. SB-mediated intratumoral gene transfer is a novel, nonviral technique that could be used to augment conventional therapy for glioblastoma or other cancers.
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PMID:Integration and long-term expression in xenografted human glioblastoma cells using a plasmid-based transposon system. 1529 73

Nestin is a member of intermediate filaments abundantly expressed in neural stem cells and glioblastomas. The nestin gene has four exons and three introns, and neural cell-specific expression is regulated by the second intron. We previously reported that nestin was invariably detected in the tumor endothelium in gliomas even though tumor cells were negative for nestin. In the present study, we further confirmed nestin immunostaining in tumor endothelium of a variety of common cancers, including lung, stomach, colon, and cervical carcinomas. We examined an endothelium-specific regulator using human umbilical vein endothelial cells (HUVECs) and human glioblastoma-derived U251 cells. In a luciferase reporter assay, the first intron plus 5' upstream promoter (5'UP) gave the highest activity, followed by 5'UP, and the second intron plus 5'UP. However, the assay values were much lower by HUVEC extracts than by U251 cell extracts. Although green fluorescent protein expression was positive over all U251 cells under either the first intron, second intron, or ubiquitously active CAG promoter, the fluorescence in HUVECs was limited to a few cells even under the first intron. This difference came from the growth feature of HUVECs which exhibit growth arrest by contact inhibition. We found that the nestin expression was specific to proliferative endothelium, by using proliferation markers in hemangioblastomas and in situ hybridization. Using an endothelial tube formation assay, tyrosine kinase domain-deleted VEGF receptor KDR effectively abolished the tube formation under the first intron. We suggest that the nestin expression in tumor endothelium is enhanced by the first intron.
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PMID:Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene. 1550 61

Despite many refinements in current therapeutic strategies, the overall prognosis for a patient with glioblastoma is dismal. Neural precursor cells (NPCs) are capable of tracking glioma tumors and thus could be used to deliver therapeutic molecules. We have engineered mouse NPCs to deliver a secreted form of tumor necrosis factor-related apoptosis-inducing ligand (S-TRAIL); S-TRAIL is optimized to selectively kill neoplastic cells. Furthermore, we have developed means to simultaneously monitor both the migration of NSCs toward gliomas and the changes in glioma burden in real time. Using a highly malignant human glioma model expressing Renilla luciferase (Rluc), intracranially implanted NPC-FL-sTRAIL expressing both firefly luciferase (Fluc) and S-TRAIL was shown to migrate into the tumors and have profound antitumor effects. These studies demonstrate the potential of NPCs as therapeutically effective delivery vehicles for the treatment of gliomas and also provide important tools to evaluate the migration of NPCs and changes in glioma burden in vivo.
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PMID:Glioma therapy and real-time imaging of neural precursor cell migration and tumor regression. 1562 35

Despite binding to receptors distinct from those of type I interferons (IFNs), human interleukins-28A, -28B and -29 (IL-28A, IL-28B and IL-29; alternatively named IFN lambda-2 {IFN-lambda2}, IFN-lambda3 and IFN-lambda1, respectively, or collectively, type III IFNs), a small family of three structurally-related cytokines, are, like IFNs, known to induce antiviral activity. To further biologically characterize IL-28A and IL-29, we compared their activities with those of IFNs in a range of human cell lines. We found that they induced antiviral activity in fewer cell lines and more weakly than IFNs; also IL-28A was less active than IL-29. Additionally, we showed IL-28A and IL-29 induced reporter genes--protein MxA promoter linked to luciferase, or interferon stimulated response element (ISRE) linked to secreted alkaline phosphatase (SEAP)--more weakly than IFN. Antiproliferative activity was induced by IFNs in most cell lines, but only in one human glioblastoma cell line, LN319, was dose-dependent IL-29-growth inhibition demonstrable. Polymerase chain reaction (PCR) quantification of messenger (m) RNA of IL-28/29 receptor subunits, IL-28Ralpha and IL-10Rbeta, indicated variable expression levels; although their expression was highest in the responsive LN319 cell line, lower but significant expression of both mRNAs was found in relatively unresponsive cell lines. In conclusion, we found IL-28A and IL-29 act similarly to IFNs, but are less effective generally and have activity in a more limited range of cell lines.
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PMID:Biological activity of interleukins-28 and -29: comparison with type I interferons. 1589 85

MYCN belongs to the MYC family of proto-oncogenes, which encode for transcription factors of the basic-helix-loop-helix-zipper (bHLHZ) class and is fundamental in the development of the peripheral and central nervous systems (PNS and CNS). While Myc is ubiquitous, MYCN has a very restricted expression pattern: it is mainly expressed during embryonic development, but then becomes downregulated, while in adults it is usually detected in B-cell development. Identification of selective inhibitors of MYCN and its mRNA and protein could be important for the development of more specific, effective and less toxic therapeutic agents for tumors of the PNS and CNS. In children, the most common tumors of the PNS and CNS are neuroblastomas and medulloblastomas, respectively. About 30% of neuroblastoma (NB) tumors present MYCN amplification/over-expression, which is associated with rapid progression and poor prognosis. N-Myc is essential during neurogenesis for the rapid expansion of progenitor cells in the brain. MYCN amplification and over-expression has been reported in medulloblastoma, and especially in the desmoplastic type. Other tumors associated with MYCN overexpression include retinoblastoma, small cell lung carcinoma, glioblastoma and certain embryonal tumors. A cell-based, N-Myc-dependent luciferase reporter gene assay to identify specific N-Myc small-molecule inhibitors has allowed identification of five compounds showing significant activity. Antisense oligodeoxynucleotides have been shown to inhibit N-Myc production and anti-tumoral activity in vitro and in vivo for NB. Peptide nucleic acids (PNA), which belong to the most recent (third) generation of nucleic acid therapeutics, form highly stable duplexes with DNA and RNA, and are resistant to degradation by nucleases and proteases. Encouraging results have been reported utilizing a PNA-based antisense strategy for inhibition of N-Myc expression in neuroblastoma.
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PMID:The MYCN oncogene as a specific and selective drug target for peripheral and central nervous system tumors. 1597 48

Glioblastoma is a fatal brain tumor that becomes highly vascularized by secreting proangiogenic factors and depends on continued angiogenesis to increase in size. Consequently, a successful antiangiogenic therapy should provide long-term inhibition of tumor-induced angiogenesis, suggesting long-term gene transfer as a therapeutic strategy. In this study a soluble vascular endothelial growth factor receptor (sFlt-1) and an angiostatin-endostatin fusion gene (statin-AE) were codelivered to human glioblastoma xenografts by nonviral gene transfer using the Sleeping Beauty (SB) transposon. In subcutaneously implanted xenografts, co-injection of both transgenes showed marked anti-tumor activity as demonstrated by reduction of tumor vessel density, inhibition or abolition of glioma growth, and increase in animal survival (P = 0.003). Using luciferase-stable engrafted intracranial gliomas, the anti-tumor effect of convection-enhanced delivery of plasmid DNA into the tumor was assessed by luciferase in vivo imaging. Sustained tumor regression of intracranial gliomas was achieved only when statin-AE and sFlt-1 transposons were coadministered with SB-transposase-encoding DNA to facilitate long-term expression. We show that SB can be used to increase animal survival significantly (P = 0.008) by combinatorial antiangiogenic gene transfer in an intracranial glioma model.
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PMID:Combinatorial antiangiogenic gene therapy by nonviral gene transfer using the sleeping beauty transposon causes tumor regression and improves survival in mice bearing intracranial human glioblastoma. 1615 Jun 49

Estradiol can protect the brain from a variety of insults by activating membrane-initiated signaling pathways, and thereby modulate gene expression and lead to functional changes in neurons. These direct neuronal effects of the hormone have been well documented; however, it is less understood what effects estradiol may have on nonneuronal cells of the central nervous system. There is evidence that estradiol levels can induce the release of glial-derived growth factors and other cytokines, suggesting that estradiol may both directly and indirectly protect neurons. To determine whether 17beta-estradiol (E2) can activate rapid signaling and modulate nonclassical transcription in astrocytes, we stably transfected the C6 rat glioblastoma cell line with human estrogen receptor (ER) alpha (C6ERalpha) or rat ERbeta (C6ERbeta). Introduction of a cAMP response element-luciferase reporter gene into C6, C6ERalpha, and C6ERbeta cells leads to the observation that E2 treatment reduced isoproterenol-stimulated luciferase activity by 35% in C6ERalpha but had no effect on reporter gene expression in C6ERbeta or untransfected C6 cells. A similar effect was seen with a membrane-impermeable estrogen (E2-BSA), suggesting the modulation of nonclassical transcription by estradiol treatment is mediated by the activation of a membrane-initiated signaling pathway. Furthermore, pretreatment with wortmannin (phosphatidylinsositol 3-kinase) or U73122 (phospholipase C) attenuated the E2-induced reduction in nonclassical transcription. We conclude that E2 treatment reduces cAMP response element-mediated transcription in glioma cells expressing ERalpha and that this reduction is dependent on the activation of membrane-initiated signaling. These findings suggest a novel model of estrogen rapid signaling in astrocytes that leads to modulation of nonclassical transcription.
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PMID:Estradiol reduces nonclassical transcription at cyclic adenosine 3',5'-monophosphate response elements in glioma cells expressing estrogen receptor alpha. 1643 53

Active Ras contributes to the malignant phenotype of glioblastoma multiforme. Recent studies showed that the Ras inhibitor farnesyl thiosalicylic acid downregulates the transcription factor hypoxia-inducible factor-1alpha, causing shutdown of glycolysis in U87 glioblastoma cells. Farnesyl thiosalicylic acid also inhibited the growth of U87 cells. The way in which Ras inhibition affects U87 cell proliferation was not clear. Here we applied a computational method in which gene expression profile clustering is combined with promoter sequence analysis to obtain global dissection of the transcriptional response to farnesyl thiosalicylic acid in U87 cells. The analysis revealed a prominent Ras-dependent cell-cycle arrest response, in which a major component is highly enriched for the binding-site signature of the transcription factor E2F1. Electrophoretic mobility shift assays together with E2F-luciferase reporter assays showed that E2F1 was inactivated by the Ras inhibitor. Inhibition of Ras by farnesyl thiosalicylic acid promoted proteasomal degradation of cyclin D1, with a concomitant decrease in phosphorylated retinoblastoma protein accompanied by downregulation of E2F1 and decreased expression of key E2F1-regulated genes critical for cell-cycle progression. U87 cell growth arrest induced by farnesyl thiosalicylic acid was overridden by constitutive expression of E2F1. Thus, downregulation of E2F1 and of hypoxia-inducible factor-1alpha represents 2 distinct arms of the antioncogenic effect of Ras inhibitors in glioblastoma.
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PMID:E2F1 identified by promoter and biochemical analysis as a central target of glioblastoma cell-cycle arrest in response to Ras inhibition. 1649 86


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