A novel oncolytic herpes simplex virus armed with the carboxyl-terminus of murine MyD116 has enhanced anti-tumour efficacy against human breast cancer cells.
A novel oncolytic herpes simplex virus armed with the carboxyl-terminus of murine MyD116 has enhanced anti-tumour efficacy against human breast cancer cells.
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DOI：
10.3892/ol.2018.8247
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发表时间：
2018-05
期刊：
影响因子：
2.9
通讯作者：
Liu R
中科院分区：
文献类型：
--
作者：
Cheng L;Jiang H;Fan J;Wang J;Hu P;Ruan Y;Liu R
溶瘤单纯疱疹病毒 1 (oHSV-1) 载体是有前途的癌症治疗剂。 γ34.5基因的缺失消除了神经毒力，但同时减弱了病毒复制。蛋白磷酸酶1调节亚基15A（也称为MyD116/GADD34）的羧基末端与γ34.5同源；因此，它可能替代γ34.5来增强病毒的复制和细胞毒性。为了研究MyD116的C端是否能够增强G47Δ对人乳腺癌细胞的抗肿瘤功效，利用细菌人工染色体和两个重组酶系统（Cre/loxP和FLPE/FRT）将γ34.5-MyD116嵌合体插入G47Δ基因组中，构建GD116突变体。还使用相同的方法创建仅含有巨细胞病毒序列的GD空突变体作为对照。接下来，评估了这两种病毒载体在乳腺癌细胞中的复制和细胞毒性。与GD空载体相比，GD116在MCF-7和MDA-MB-231细胞中具有增强的复制能力和溶瘤活性。在MOI为0.01和0.1的GD116感染后第五天，分别杀死49.2%和82.8%的MCF-7细胞，在MOI为0.1和0.3的GD116分别杀死35.0%和50.2%的MDA-MB-231细胞。此外，感染后48小时，γ34.5-MyD116嵌合体的插入促进了MDA-MB-468中的病毒复制，但没有观察到细胞毒性作用增加。本研究结果表明，MyD116基因的C末端可以取代oHSV-1的γ34.5基因的相应结构域，以促进病毒在感染细胞中的复制。此外，携带γ34.5-MyD116嵌合体的新型病毒突变体GD116在体外增强了对人乳腺癌细胞的抗肿瘤功效。
Oncolytic herpes simplex virus-1 (oHSV-1) vectors are promising therapeutic agents for cancer. The deletion of the γ34.5 gene eliminates the neurovirulence but attenuates virus replication at the same time. The carboxyl-terminus of protein phosphatase 1 regulatory subunit 15A (also known as MyD116/GADD34) is homologous to that of γ34.5; hence, it may substitute for γ34.5 to enhance the replication and cytotoxicity of the virus. To investigate whether the C-terminus of MyD116 can enhance the anti-tumour efficacy of G47Δ on human breast cancer cells, a GD116 mutant was constructed by inserting a γ34.5-MyD116 chimaera into the G47Δ genome using a bacterial artificial chromosome and two recombinase systems (Cre/loxP and FLPE/FRT). A GD-empty mutant containing only the cytomegalovirus sequence was also created as a control using the same method. Next, the replication and cytotoxicity of these two virus vectors were evaluated in breast cancer cells. Compared with the GD-empty vector, GD116 possessed an enhanced replication capability and oncolytic activity in MCF-7 and MDA-MB-231 cells. On the fifth day after infection with GD116 at MOIs of 0.01 and 0.1, 49.2 and 82.8% of MCF-7 cells, respectively, were killed, with 35.0 and 50.2% of MDA-MB-231 cells, respectively, killed by GD116 at MOIs of 0.1 and 0.3. Additionally, the insertion of the γ34.5-MyD116 chimaera promoted virus replication in MDA-MB-468 at 48 h after infection, although no increased cytotoxic effect was observed. The findings of the present study indicate that the C terminus of the MyD116 gene can be substituted for the corresponding domain of the γ34.5 gene of oHSV-1 to promote the replication of the virus in infected cells. Furthermore, the novel virus mutant GD116 armed with a γ34.5-MyD116 chimaera has enhanced anti-tumour efficacy against human breast cancer cells in vitro.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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DOI：
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发表时间：
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期刊：
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