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

被引:31
作者
Ng, S. S. M.
Gao, Y.
Chau, D. H. W.
Li, G. H. Y.
Lai, L. H.
Huang, P. T.
Huang, C. F.
Huang, J. J.
Chen, Y. C.
Kung, H. F.
Lin, M. C. M.
机构
[1] Univ Hong Kong, Dept Chem, Open Lab Chem Biol, Hong Kong, Hong Kong, Peoples R China
[2] Univ Hong Kong, Dept Microbiol, Hong Kong, Hong Kong, Peoples R China
[3] E China Normal Univ, Inst Mol & Chem Biol, Shanghai, Peoples R China
[4] Beijing Inst Biotechnol, Dept Tumor & Mol Biol, Beijing, Peoples R China
[5] Chinese Univ Hong Kong, State Key Lab Oncol So China, Shatin, Hong Kong, Peoples R China
[6] Chinese Univ Hong Kong, Ctr Emerging Infect Dis, Shatin, Hong Kong, Peoples R China
关键词
glioblastoma; AAV; hTERTC27;
D O I
10.1038/sj.cgt.7701038
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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.
引用
收藏
页码:561 / 572
页数:12
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