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Tumor Biology |
Neuro-Oncology Program, Department of Oncology, University Children's Hospital Zürich, 8032 Zürich, Switzerland
3 Send correspondence to Michael Grotzer, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland (Michael.Grotzer{at}kispi.unizh.ch).
Abstract
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.
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