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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study is to investigate the effect of the p21 gene transfection on the growth of cultured human glioma cell lines, and analyze the telomerase activity, and detection of telomerase components in p21 transfectant. The p21 gene was transfected into human glioma cell lines, U251MG and T98G with our novel liposome. The cell growth was assessed by counting the number of trypan blue-excluding cells in a hemocytometer and flow cytometry analysis. The expression of P21 protein and its mRNA were examined by Western and Northern blot analysis. The telomerase activity was assayed by TRAP (telomerase repeat amplification protocol)/TRAP-HPA (hybridization protection assay) method qualitatively and quantitatively. The length of telomere was measured by Southern blot analysis. The expression of telomerase components (hTERT, hTERC and TEP1) were examined by RT-PCR (reverse transcriptase-polymerase chain reaction). The p21 transfectant demonstrated the expression of P21 protein and its mRNA. The p21 transfection of human glioma cells results in growth inhibition and G0/G1 arrest. The p21 transfectant revealed a decrease of telomerase activity and hTERT expression as compared with control cells. These results suggest that p21 transfection induces G0/G1 arrest in human glioma cells which associates with the reduction in the telomerase activity and hTERT expression.
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PMID:Growth inhibition of human glioma cells by transfection-induced P21 and its effects on telomerase activity. 1093 98

Gliomas remain one of the deadliest forms of cancer. Improved therapeutics will require a better understanding of the molecular nature of these tumors. We, therefore, mimicked the most common genetic changes found in grade III-IV gliomas, disruption of the p53 and RB pathways and activation of telomere maintenance and independence from growth factors, through the ectopic expression of the SV40 T/t-Ag oncogene, an oncogenic form of H-ras (H-ras(V12G)), and the human telomerase catalytic subunit hTERT in normal human astrocytes. The resulting cells displayed many of the hallmarks of grade III-IV gliomas, including greatly expanded life span and growth in soft agar and, most importantly, were tumorigenic with pathology consistent with grade III-IV neuroectodermal tumors in mice. This model system will, for the first time, allow the biological significance of selected genetic alterations to be studied in human gliomas.
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PMID:A genetically tractable model of human glioma formation. 1132 17

To facilitate the study of human endothelial cells we have used a replication defective retrovirus encoding the catalytic subunit of telomerase (hTERT) to derive populations of telomerase-immortalized human microvascular endothelial (TIME) cells. Whereas parental HMVECs became senescent on average within 35-45 population doublings (PDs), TIME cells have continued to proliferate for at least 200 PDs. TIME cells express readily detectable telomerase activity but display only a modest increase in telomere length. Karyotypic analysis reveals the cells to have a normal complement of human chromosomes with no evidence of gross genetic abnormalities. Furthermore, TIME cells retain many of the characteristics of the primary endothelial cells from which they were derived. For example, they express a panel of characteristic endothelial cell surface marker proteins such as CD31/PECAM-1 and alpha(v)beta3-integrin. In addition, TIME cells express receptors for low-density lipoprotein (LDL) receptor as they are competent for receptor-mediated endocytosis of fluorescent acetylated LDL. Importantly, when plated on matrigel, TIME cells undergo tubule formation. Moreover, when cocultured in the presence of human glioma cells, but not primary human astrocytes, TIME cells are induced to form stable tubules. Detachment of TIME cells from extracellular matrix leads to a form of programmed cell death known as anoikis. Conditional activation of the protein kinase Akt (Akt:ER*) significantly inhibited the onset of TIME cell anoikis under these conditions. We believe that the ability of hTERT to immortalize primary human endothelial cells, and the fact that such cells retain the endothelial characteristics of the cells from which they were derived, will greatly facilitate the analysis of human endothelial cell biology in vitro.
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PMID:Induction of tubulogenesis in telomerase-immortalized human microvascular endothelial cells by glioblastoma cells. 1179 43

Telomerase is implicated in the development of cellular immortality and oncogenesis. It has been shown that telomerase activity is considerably higher in the tissue of many different cancers than in normal tissue, and that the inhibition or downregulation of telomerase activity can prevent the malignant proliferation of tumor cells. Antisense oligonucleotides have been widely used in suppressing the expression of genes and, therefore, in the present research, we evaluated the effect of antisense human telomerase RNA (hTR) on glioma cell growth in vitro and in vivo. We showed that antisense hTR cDNA significantly inhibited TJ905 human glioma cell proliferation in vitro and tumor growth in vivo, as determined by MTT assay and by measuring the volume of glioma in nude mice. Consistent with these results, we found that telomerase activity and the mRNA levels of hTR and hTERT (human telomerase reverse transcriptase) expression were markedly decreased in tumor cells treated with antisense hTR cDNA, as assessed by TRAP (telomeric repeat amplification protocol) assay and RT-PCR (reverse transcription-polymerase chain reaction) analysis. Our study conclusively demonstrates that antisense hTR effectively inhibits the growth of human glioma cells in vitro and in vivo and, thus, may be potentially used for gene therapy of malignant gliomas and other cancers.
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PMID:Antisense telomerase RNA inhibits the growth of human glioma cells in vitro and in vivo. 1659 39

Although scientific advances have recognised the prognostic power of telomerase activity in different cancers, as yet there has been no investigation regarding the expression variation of telomerase subunits in glioma tissues and cell lines. In this study, a recurrent anaplastic ependymoma and seven glioblastoma biopsy samples, four cell lines and four controls including two normal brain tissues were analysed for telomerase subunit expression profiles together with telomerase activity. Since telomerase activity is linked to tumourgenesis, the genes were analysed with respect to their expression variation. TEP1 was expressed in all glioma cell lines and 70% of glioblastoma tissues, in addition to the control brain tissues. Tankyrase was expressed in 85% of the glioblastoma tissues and was down-regulated in the recurrent anaplastic ependymoma tissue control cell lines. However, it was expressed in the control tissues. Dyskerin was expressed in all cell lines and tissues apart from U87-MG and NHA cells and the recurrent anaplastic ependymoma tissue. As expected, PARP1 and GAPDH showed constitutive expression throughout all cell lines and tissues since both are known to be housekeeping genes. hTERT was expressed in all glioma cell lines and tissues but was absent in the control cells and tissues. Telomerase activity was absent in IPDDC-A2 cells and 57% of the glioblastoma tissues. These results suggest that hTERT expression and not telomerase activity possibly represents a simple and reliable biological diagnostic tool.
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PMID:Telomerase subunits expression variation between biopsy samples and cell lines derived from malignant glioma. 1719 47

Hypoxia-inducible factor-1alpha (HIF-1alpha) has been implicated in the transcriptional regulation of the telomerase reverse transcriptase (hTERT) gene expression and telomerase activity, essential elements for cellular immortalization and transformation. However, controversial results were obtained in different studies. Moreover, it is totally unclear whether HIF-2alpha, the paralog of HIF-1alpha, plays a role in regulating hTERT expression. In the present study, we found that hypoxic treatment enhanced hTERT mRNA expression and telomerase activity in three renal cell carcinoma (RCC) cell lines with different genetic backgrounds. Both HIF-1alpha and HIF-2alpha were capable of significantly increasing the hTERT promoter activity in these cells. Moreover, depleting HIF-2alpha led to a down-regulation of hTERT mRNA level in RCC A498 cells expressing constitutive HIF-2alpha. It was found that HIF-2alpha bound to the hTERT proximal promoter and enhanced the recruitment of the histone acetyltransferase p300 and histone H3 acetylation locally in A498 cells treated with hypoxia. Increased levels of hTERT mRNA were observed in two of three hypoxia-treated malignant glioma cell lines. However, HIF-1alpha stimulated whereas HIF-2alpha inhibited the hTERT promoter activity in these glioma cell lines. Ectopic expression of HIF-2alpha resulted in diminished hTERT expression in glioma cells. Collectively, HIF-1alpha activates hTERT and telomerase expression in both RCC and glioma cells, and HIF-2alpha enhances hTERT expression in RCC cells, whereas it represses the hTERT transcription in glioma cells. These findings reveal a complex relationship between HIF-1alpha/2alpha and hTERT/telomerase expression in malignant cells, which may have both biological and clinical implications.
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PMID:The opposing effect of hypoxia-inducible factor-2alpha on expression of telomerase reverse transcriptase. 1769 5

5-Aza-2'-deoxycytidine (5azadC) inhibits DNA methyltransferase and subsequently induces the expression of genes silenced by methylation. While treatment with 5azadC downregulated hTERT and upregulated MGMT expression in two glioma cell lines, there was no change in the expression of these two genes in the normal cell line. However, cell viability was reduced as a result of 5azadC treatment in all three cell lines. 5azadC treatment reduced telomerase expression and activity and subsequently enhanced chemosensitivity towards cisplatin, taxol and tamoxifen but not with the alkylating agents temozolomide (TMZ), carmustine and chlorambucil. To further evaluate the effect of these findings, the level of hTERT and MGMT expression was measured in a recurrent anaplastic ependymoma, seven glioblastoma and two normal brain tissues. While four of eight gliomas and one of the normal tissues expressed MGMT, hTERT was expressed in all gliomas but not in the normal brain tissue. Results of this study suggest that taxol together with 5azadC may be a good therapeutic combination for glioma. In addition, the work on cell lines can be repeated on tissues utilizing hTERT as the therapeutic target for demethylation using 5azadC in glioma.
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PMID:Epigenetic silencing of telomerase and a non-alkylating agent as a novel therapeutic approach for glioma. 1802 53

The amplification of hTERT was detected in glioma tissues, although telomerase activity was not always found within these specimens. The aim of this study was to correlate the level of hTERT transcription with telomerase activity in two glioma age groups. hTERT was significantly transcribed at similar copy numbers in both age groups. However, these mRNAs translated to telomerase in 100% of the young compared to only 25% of the older patients. While hTERT transcription correlated directly to telomerase protein level and activity, as well as longer telomeres in the young group, such correlations were missing in the older group.
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PMID:Differential hTERT mRNA processing between young and older glioma patients. 1843 20

This study assessed the prognostic value of several markers involved in gliomagenesis, and compared it with that of other clinical and imaging markers already used. Four-hundred and sixteen adult patients with newly diagnosed glioma were included over a 3-year period and tumour suppressor genes, oncogenes, MGMT and hTERT expressions, losses of heterozygosity, as well as relevant clinical and imaging information were recorded. This prospective study was based on all adult gliomas. Analyses were performed on patient groups selected according to World Health Organization histoprognostic criteria and on the entire cohort. The endpoint was overall survival, estimated by the Kaplan-Meier method. Univariate analysis was followed by multivariate analysis according to a Cox model. p14(ARF), p16(INK4A) and PTEN expressions, and 10p 10q23, 10q26 and 13q LOH for the entire cohort, hTERT expression for high-grade tumours, EGFR for glioblastomas, 10q26 LOH for grade III tumours and anaplastic oligodendrogliomas were found to be correlated with overall survival on univariate analysis and age and grade on multivariate analysis only. This study confirms the prognostic value of several markers. However, the scattering of the values explained by tumour heterogeneity prevents their use in individual decision-making.
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PMID:Prognostic molecular markers with no impact on decision-making: the paradox of gliomas based on a prospective study. 1850 88

Paired box (PAX) developmental genes are frequently expressed in cancers and confer survival advantages on cancer cells. We have previously found that PAX genes are deregulated in glioma. We have now investigated the expression of PAX genes in glioma and their role in telomere maintenance. The mRNA level of PAX8 showed a positive correlation with telomerase activity in glioma biopsies (r(2) = 0.75, P < 0.001) and in established glioma cell lines (r(2) = 0.97, P = 0.0025). We found that PAX8 is able to coordinately transactivate the promoter for both the telomerase catalytic subunit (hTERT) and the telomerase RNA component (hTR) genes. By electrophoretic mobility shift assay, quantitative PCR, and a telomerase activity assay, we show that PAX8 binds directly to the hTERT and hTR promoters, up-regulating hTERT and hTR mRNA, as well as telomerase activity. Additionally, PAX8 small interfering RNA down-regulated hTERT and hTR. Collectively, these results show that PAX8 may have a role in telomerase regulation.
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PMID:PAX8 regulates telomerase reverse transcriptase and telomerase RNA component in glioma. 1863 25


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