Expression of transcription factor E2F1 and telomerase in glioblastomas: Mechanistic linkage and prognostic significance

University of California, San Francisco, San Francisco, California, United States
Journal of the National Cancer Institute (Impact Factor: 12.58). 12/2005; 97(21):1589-600. DOI: 10.1093/jnci/dji340
Source: PubMed


Several tumor suppressor pathways have been identified as modulators of telomerase function. We examined the functional role of the retinoblastoma-E2F1 pathway in regulating telomerase activity in malignant gliomas.
Adenovirus vectors were used to transfer cDNAs into human glioblastoma and sarcoma cells. Telomerase activity was assessed with a telomere repeat amplification protocol. Promoter activity in cancer cells was assessed with promoter-luciferase reporter constructs. Promoter binding was assessed with the chromatin immunoprecipitation (ChIP) assay. We isolated astrocytes from E2F1 transgenic mice and normal mice for in vivo studies. We evaluated the expression of E2F1 and hTERT (the catalytic subunit of human telomerase) mRNAs by reverse transcriptase-polymerase chain reaction and proteins in human glioblastoma samples by immunoblot analysis. Associations between survival among 61 glioblastoma multiforme patients and expression of E2F1 and hTERT mRNA and protein were examined with Kaplan-Meier analysis, the log-rank test, and Cox proportional hazards regression models. All statistical tests were two-sided.
Ectopic E2F1 expression increased hTERT promoter activity in cancer cells. We detected an interaction between E2F1 protein and the hTERT promoter. Transgenic E2F1 astrocytes contained functional telomerase protein. E2F1 mRNA expression and hTERT mRNA expression were statistically significantly correlated in human glioblastoma specimens (R = .8; P < .001). Longer median survival was statistically significantly associated with lower E2F1 mRNA expression in tumors (103.6 weeks) rather than with higher expression (46.1 weeks) (difference = 57.5 weeks; 95% confidence interval [CI] = 14.7 to 159.7; log-rank P = .002). E2F1 mRNA was the only factor that was statistically significantly associated with overall survival in a multivariable model (P = .04). Among 27 patients with glioblastoma multiforme samples, the expression of E2F1 protein was statistically significantly associated with survival (log-rank P < .001).
E2F1 may participate in telomerase activity regulation in malignant glioma cells. Its expression appears to be strongly associated with the survival of patients with malignant brain tumors.

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    • "Ju-Seog Lee et al reported that the expression signature of E2F1 and its associated genes predicted superficial to invasive progression of bladder tumors [8]. In another study, E2F1 may participate in telomerase activity regulation in malignant glioma cells and its expression seemed to be strongly associated with the survival of patients with malignant brain tumors [18]. In a study that aimed to predict the outcome in Korean women who underwent surgery for breast carcinoma, the E2F1-positive group had less tumor recurrences, lymph node metastasis during follow-up, and distant metastasis than the E2F1-negative group [19]. "
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    ABSTRACT: Transcription factor E2F1 exerts effects on many types of cancers. As an upstream regulator of a host of genes, E2F1 can trigger diverse aberrant transcription processes that may dominate malignancy. Clear cell renal cell carcinoma (ccRCC) is the most common subtype in renal cell carcinoma which displays high malignancy and has a shortage of biomarkers in clinics. Our study aimed to explore the function of E2F1 in ccRCC and its correlation with clinicopathological parameters. Transcription factor E2F1 was mainly distributed in cancer cell nucleus and mRNA expression significantly increased in 72 cases of clear cell renal cell carcinoma (ccRCC) tissues compared with adjacent non-cancerous kidney tissues (p<0.001). The protein expression was consistent with mRNA expression. Further analysis in 92 cases indicated that E2F1 mRNA level expression was associated with the tumor pathologic parameters embracing diameter, Fuhrman tumor grade, pT stage, TNM stage grouping and macrovascular infiltration (MAVI). These surgical specimens had high grade tumors accompanied with an elevated E2F1 expression. Moreover, E2F1 transfection was found to contribute significantly to cancer cell proliferation, migration and invasion in vitro. Overexpression of E2F1 may be a key event in the local and vascular infiltration of ccRCC indicated by the activation of matrix metalloproteinase (MMP) 2 and MMP9. These findings highlighted the implication of E2F1's function in the metastatic process. Furthermore, the clinical relevance of E2F1 in ccRCC pointed to a potential new therapeutic target.
    PLoS ONE 09/2013; 8(9):e73436. DOI:10.1371/journal.pone.0073436 · 3.23 Impact Factor
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    • "Recent advances have implicated a defined set of oncogenic pathways in the underlying biology of this tumor group [2]. Among these crucial signaling networks, the Akt pathway and E2F1 have emerged as being particularly important in glioma pathogenesis, which is correlated with poor prognosis in multiple glioma subtypes [3,4]. "
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    ABSTRACT: MicroRNAs have recently emerged as key regulators of cancers, miR-329 located on 14q32.31 is one of down-regulated miRNAs in glioma, but the function and molecular mechanisms of miR-329 in determining the malignant phenotype of human glioma are elusive. This study therefore was conducted to investigate the role of miR-329 in biological behaviors of human glioma LN18 and T98G cell lines and its molecular mechanisms. Nine patients with GBM were analyzed for the expression of miR-329 by quantitative RT--PCR. MiR-329 overexpression was established by transfecting miR-329 precursor into LN18 and T98G cells, and its effects on cell proliferation were studied using MTT assay, anchorage-independent growth ability assay, colony formation assays, Bromodeoxyuridine labeling and immunofluorescence.The effects of miR-329 on cell cycle were studied by flow cytometry. The target of miR-329 was determined by luciferase assays. The regulation of miR-329 on Akt pathway was determined by western blot. The E2F1 was identified as the target of miR-329. Overexpression of miR-329 blocked G1/S transition in LN18 and T98G cell lines, dramatically suppressed cell proliferation and the ability of colony formation. MiR-329 significantly decreased the phosphorylation levels of intracellular kinases Akt and expression of cyclin D1, but the expression of p21 was upregulated, cell growth was suppressed by inhibiting E2F1-mediated Akt pathway. MiR-329 may inhibit cell proliferation in human glioma cells through regulating E2F1-mediated suppression of Akt pathway.
    Journal of Translational Medicine 07/2013; 11(1):172. DOI:10.1186/1479-5876-11-172 · 3.93 Impact Factor
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    • "Inactivation of Rb (phosphorylated Rb) in cancer cells results in the deregulation of the transcription factor E2F1, which controls the expression of genes involved in cell cycle and proliferation [19]. Actually, alternation of the CDK4/6-pRb-E2F1 pathway has been identified in the majority of human malignancies including GBM [19] [20]. However, whether knockdown of oncoprotein EZH2 could trigger inactivation of CDK4/6-pRb-E2F1 pathway subsequently affecting GBM tumorigenicity remains unknown. "
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    ABSTRACT: Deregulation of microRNAs (miRNAs) is implicated in tumor progression. We attempt to indentify the tumor suppressive miRNA not only down-regulated in glioblastoma multiforme (GBM) but also potent to inhibit the oncogene EZH2, and then investigate the biological function and pathophysiologic role of the candidate miRNA in GBM. In this study, we show that miRNA-138 is reduced in both GBM clinical specimens and cell lines, and is effective to inhibit EZH2 expression. Moreover, high levels of miR-138 are associated with long overall and progression-free survival of GBM patients from The Cancer Genome Atlas dataset (TCGA) data portal. Ectopic expression of miRNA-138 effectively inhibits GBM cell proliferation in vitro and tumorigenicity in vivo through inducing cell cycles G1/S arrest. Mechanisms investigation reveals that miRNA-138 acquires tumor inhibition through directly targeting EZH2, CDK6, E2F2 and E2F3. Moreover, an EZH2-mediated signal loop, EZH2-CDK4/6-pRb-E2F1, is probably involved in GBM tumorigenicity, and this loop can be blocked by miRNA-138. Additionally, miRNA-138 negatively correlates to mRNA levels of EZH2 and CDK6 among GBM clinical samples from both TCGA and our small amount datasets. In conclusion, our data demonstrate a tumor suppressive role of miRNA-138 in GBM tumorigenicity, suggesting a potential application in GBM therapy.
    Biochimica et Biophysica Acta 05/2013; 1832(10). DOI:10.1016/j.bbadis.2013.05.015 · 4.66 Impact Factor
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