Journal Article

Expression of Transcription Factor E2F1 and Telomerase in Glioblastomas: Mechanistic Linkage and Prognostic Significance

Marta M. Alonso, Juan Fueyo, Jerry W. Shay, Kenneth D. Aldape, Hong Jiang, Ok-Hee Lee, David G. Johnson, Jing Xu, Yasuko Kondo, Takao Kanzawa, Satoru Kyo, B. Nebiyou Bekele, Xian Zhou, Janice Nigro, J. Matthew McDonald, W. K. Alfred Yung and Candelaria Gomez-Manzano

in JNCI: Journal of the National Cancer Institute

Volume 97, issue 21, pages 1589-1600
Published in print November 2005 | ISSN: 0027-8874
Published online November 2005 | e-ISSN: 1460-2105 | DOI: http://dx.doi.org/10.1093/jnci/dji340
Expression of Transcription Factor E2F1 and Telomerase in Glioblastomas: Mechanistic Linkage and Prognostic Significance

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Background: 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. Methods: 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. Results: 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). Conclusions: 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.

Journal Article.  9067 words.  Illustrated.

Subjects: Medical Oncology

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