Dependence of efficient adenoviral gene delivery in malignant glioma cells on the expression levels of the Coxsackievirus and adenovirus receptor
Dependence of efficient adenoviral gene delivery in malignant glioma cells on the expression levels of the Coxsackievirus and adenovirus receptor
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DOI：
10.3171/jns.2000.92.6.1002
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发表时间：
2000-06-01
影响因子：
4.1
通讯作者：
Abe, H
中科院分区：
文献类型：
--
作者：
Asaoka, K;Tada, M;Abe, H
目的。重组腺病毒因其高效的基因递送而被用作多种癌症基因治疗的有效载体。为了研究基因治疗在恶性神经胶质瘤中的可行性，作者使用 15 种不同的高级神经胶质瘤细胞系检测了腺病毒转导的野生型 p53 肿瘤抑制基因的抗增殖作用。尽管在 15 个细胞系中的 5 个中观察到与高腺病毒 p53 转导效率相关的生长抑制，但在其余 10 个细胞系中未观察到这种情况。为了阐明潜在机制，我们检查了柯萨奇病毒和腺病毒受体（CAR）（腺病毒的主要受体）以及整合素αvβ3和αvβ5（促进腺病毒内化）的表达水平。在测试的细胞系中，CAR基因的表达水平与腺病毒基因转导效率密切相关，而整合素的表达水平则不然。在带有突变体p53的U251MG细胞中，CAR表达通过野生型p53转导而降低，并且在具有内源性野生型p53的LN443细胞中通过p53的反义抑制而增加。结论。这项研究的结果表明，CAR 表达是人类恶性胶质瘤基于腺病毒的基因治疗转导效率的关键决定因素。
Object. Recombinant adenovirus is used as a competent vector in a wide spectrum of cancer gene therapies because of its high efficiency in gene delivery. To study the feasibility of gene therapy in malignant gliomas, the authors examined the antiproliferative effect of the adenovirally transduced wild-type p53 tumor suppressor gene by using 15 different high-grade glioma cell lines.Methods. Although growth suppression in association with a high adenoviral p53 transduction efficiency was seen in five of 15 cell lines, it was not observed in the remaining 10 cell lines. To clarify the underlying mechanism, we examined the expression levels of the Coxsackievirus and adenovirus receptor (CAR), which is the primary receptor for adenovirus, and of the integrins alpha v beta 3 and alpha v beta 5, which promote adenoviral internalization. The expression level of the CAR gene showed a close correlation to adenoviral gene transduction efficiency in the tested cell lines, whereas the expression levels of the integrins did not. The CAR expression was decreased by wild-type p53 transduction in U251MG cells harboring mutant p53 and increased by antisense inhibition of p53 in LN443 cells with endogenous wild-type p53.Conclusions. The results of this study indicate that CAR expression is a critical determinant of transduction efficiencies in adenovirus-based gene therapy for human malignant gliomas.