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Telomere
maintenance in childhood primitive neuroectodermal brain tumors
Domenico Didiano, Tarek Shalaby, Doris Lang, Michael A. Grotzer
Neuro-Oncology Program, Department of Oncology, University
Children’s Hospital Zürich, 8032
Zürich, Switzerland
Primitive neuroectodermal tumors (PNETs), including medulloblastoma (PNET/MB)
and supratentorial PNET (sPNET), are the most common malignant brain tumors of
childhood.
The stabilization of telomere lengths by telomerase activation is an important
step in carcinogenesis and cell immortalization.
Epigallocatechin gallate (EGCG), the major polyphenol in green tea, is a
telomerase inhibitor with antiproliferative and anticarcinogenic effects against
different types of cancer.
In this study, we used real-time reverse transcriptase-polymerase chain reaction
to measure the mRNA expression of the human telomerase reverse transcriptase
(hTERT) in 50 primary PNET samples (43 PNET/MB, 7 sPNET), 14 normal human brain
samples, and 6 human PNET cell lines.
Compared to normal human cerebellum, 38/50 (76%) primary PNET samples had
≥ 5-fold upregulated hTERT mRNA expression.
We then examined PNET cell lines for telomerase activity using a quantitative
telomeric repeat amplification protocol (TRAP), and for telomere length using
terminal restriction fragment analysis.
While a positive correlation between hTERT mRNA expression and telomerase
activity was detected in PNET cell lines, no correlation was found between
telomerase activity and telomere length.
Treatment of PNET cell lines with EGCG resulted in a dose-dependent inhibition
of telomerase activity at micromolar levels.
Although EGCG displayed strong proliferation inhibitory effects against
TRAP-positive PNET cell lines, it had no significant effect against
TRAP-negative D425 cells.
These results provide evidence for a possible role of telomerase in the
pathogenesis of most PNETs and indicate that subsets of PNETs maintain telomere
length by alternative mechanisms.
Inhibition of telomerase function represents a novel experimental therapeutic
strategy in childhood PNETs that warrants further investigation.
© 2003 Duke University Press
Source: http://dandini.ingentaselect.com/cgi-bin/linker?ini=dup_no&reqidx=/cw/dup/15228517/v6n1/s1/p1
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