1. ¹Department of Chemistry, Open Laboratory of Chemical Biology, The University of Hong Kong, Pokfulam, Hong Kong, China
2. ²Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong, China
3. ³Institute of Molecular and Chemical Biology, East China Normal University, Shanghai, China
4. ⁴Department of Tumor and Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
5. ⁵State Key Laboratory of Oncology in Southern China, The Chinese University of Hong Kong, Shatin, China
6. ⁶Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, China

Correspondence: Dr MCM Lin, Department of Chemistry, The University of Hong Kong, 8/F, Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong, China. E-mail: mcllin@hkusua.hku.hk; Professor HF Kung, Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, China. E-mail: hkung@cuhk.edu.hk

⁷These authors contributed equally to this work.

Received 3 July 2006; Revised 27 November 2006; Accepted 11 February 2007; Published online 23 March 2007.

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.