A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide
A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide
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DOI：
10.1038/sj.cgt.7701038
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发表时间：
2007-06-01
影响因子：
6.4
通讯作者：
Lin, M. C. M.
中科院分区：
文献类型：
--
作者：
Ng, S. S. M.;Gao, Y.;Lin, M. C. M.
多形性胶质母细胞瘤是人类脑肿瘤中最具侵袭性的一种，目前尚无有效的治疗方法。以前，我们已经证明，过表达的C-末端片段的人端粒酶逆转录酶（hTERTC 27）抑制人宫颈癌HeLa细胞的生长和致瘤性。在本研究中，hTERTC 27介导的癌症基因治疗的治疗效果和分子机制进一步探讨在体内建立的人胶质母细胞瘤裸鼠移植瘤。我们发现肿瘤内注射携带hTERTC 27的腺相关病毒（rAAV-hTERTC 27）在减少皮下移植的胶质母细胞瘤肿瘤的生长方面是非常有效的。组织学分析显示，rAAV-hTERTC 27处理导致肿瘤样品中严重的坏死、凋亡、多形核中性粒细胞浸润和微血管密度降低。为了研究rAAV-hTERTC 27介导的抗肿瘤作用的分子机制，我们采用基因芯片技术分析了rAAV-hTERTC 27处理的肿瘤组织和细胞系的基因表达谱，并与对照rAAV-green fluorescent protein处理的肿瘤组织和细胞系的基因表达谱进行了比较。我们的研究结果表明hTERTC 27通过复杂的机制发挥其作用，涉及调控细胞凋亡、细胞粘附、细胞周期、免疫反应、代谢、信号转导、转运、转录和端粒维持的基因。
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.