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A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide

Abstract

Glioblastoma multiforme is the most aggressive form of human brain tumor, which has no effective cure. Previously, we have demonstrated that overexpression of the C-terminal fragment of the human telomerase reverse transcriptase (hTERTC27) inhibits the growth and tumorigenicity of human cervical cancer HeLa cells. In this study, the therapeutic effect and molecular mechanisms of hTERTC27-mediated cancer gene therapy were further explored in vivo in established human glioblastoma xenografts in nude mice. We showed that intratumoral injection of adeno-associated virus carrying hTERTC27 (rAAV-hTERTC27) is highly effective in reducing the growth of the subcutaneously transplanted glioblastoma tumors. Histological analyses showed that rAAV-hTERTC27 treatment leads to profound necrosis, apoptosis, infiltration of polymorphonuclear neutrophils and reduced microvessel density in the tumor samples. To study the molecular mechanism of rAAV-hTERTC27-mediated antitumor effects, we analyzed the global gene expression profiles of the rAAV-hTERTC27-treated tumor tissues and cell line as compared with that of the control rAAV-green fluorescent protein-treated samples by DNA microarray. Our results suggest that hTERTC27 exerts its effect through complex mechanisms, which involve genes regulating apoptosis, cell adhesion, cell cycle, immune responses, metabolism, signal transduction, transport, transcription and telomere maintenance.

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Acknowledgements

We thank the Genome Research Center (HKU) for conducting the microarray analysis. The work was supported by Innovation and Technology Fund (ITS/105/02) to MCL and grants from the Hong Kong Research Grant Council (CUHK 7422/03M to HFK; HKU 7243/02M to MCL), Li Ka Shing Institute of Health Sciences (to HFK), Shanghai Metropolitan Fund for Research and Development (04JC14096) and Guangzhou Metropolitan Fund (2005Z1-E0131).

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Correspondence to H F Kung or M C M Lin.

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Ng, S., Gao, Y., Chau, D. et al. A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide. Cancer Gene Ther 14, 561–572 (2007). https://doi.org/10.1038/sj.cgt.7701038

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