依赖hTERT启动子的新型溶瘤单纯疱疹病毒的构建和功能研究
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摘要
背景：近20年来,溶瘤病毒疗法已经被证实是一种新型有效的肿瘤治疗策略。如腺病毒、单纯疱疹病毒和新城疫病毒等溶瘤病毒能够在肿瘤细胞中复制增殖并直接杀伤肿瘤细胞。目前,毒性过高仍然是溶瘤病毒应用中的主要障碍。为解决此问题,我们构建了一种新型溶瘤单纯疱疹病毒oHSV1_hTERTp_ICP4,该病毒基因组中关键复制基因ICP4由肿瘤特异性启动子hTERT启动子调控,这使得重组新病毒可以选择性地在肿瘤细胞复制增殖,其安全性得到大幅度提高。并且,我们通过体内外实验评估了oHSV1_hTERTp_ICP4的溶瘤活性和肿瘤特异性。
方法：本研究主要通过质粒构建和同源重组技术完成重组新病毒oHSV1_hTERTp_ICP4和两种具有示踪作用的病毒oHSV1_hTERTp_ICP4_CMVp_eGFP和oHSV1_hTERTp_ICP4_CMVp_Luc2的构建工作；通过CCK-8细胞增殖实验检测oHSV1_hTERTp_ICP4对多种肿瘤和正常细胞系的杀伤能力；通过滴度测定方法检测oHSV1_hTERTp_ICP4在多种细胞系中的增殖情况；通过流式细胞术和激光共聚焦技术明确oHSV1_hTERTp_ICP4对正常人血细胞的感染复制情况；通过动物实验初步评价oHSV1_hTERTp_ICP4在BGC823肿瘤模型中的抗肿瘤效果,并使用oHSV1_hTERTp_ICP4_CMVp_Luc2示踪检测新病毒在荷瘤裸鼠中不同组织内的复制表达情况；通过实时定量PCR实验检测oHSV1_hTERTp_ICP4感染细胞后对hTERT启动子活性的影响；最后通过AnnexinV+PI双染法检测oHSV1_hTERTp_ICP4的细胞毒作用与细胞坏死和凋亡间的关系。
结果：(1)本研究成功构建了含有hTERT启动子的新病毒oHSV1_hTERTp_ICP4及具有示踪作用的病毒oHSV1_hTERTp_ICP4_CMVp_eGFP和oHSV1_hTERTp_ICP4_CMVp_Luc2。(2) oHSV1_hTERTp_ICP4在端粒酶阳性肿瘤细胞系中显示出与原病毒oHSV1-17+相似的溶瘤活性；并且在端粒酶阴性细胞系中,没有造成明显的损伤(正常剂量MOI=0.1,1),而oHSV1-17+却显示出了明显的杀伤作用。另外,我们发现oHSV1_hTERTp_ICP4在多种细胞中的增殖能力和细胞毒作用具有一致性。(3)经流式检测,在正常人血细胞中oHSV1-17+-GFP感染后出现了少量的绿色荧光细胞,而oHSV1_hTERTp_ICP4_CMVp_eGFP感染后几乎没有绿色荧光细胞被发现；另外,激光共聚焦结果显示新病毒只在掺杂入的肿瘤细胞中显著增殖,而在正常细胞中未发生显著增殖,以上结果表明新病毒在正常人血细胞中具有良好的安全性。(4)在荷BGC823肿瘤裸鼠模型中,oHSV1_hTERTp_ICP4显示出了与oHSV1-17+相似的抑瘤效果,但在生存期上却明显优于后者；小鼠活体成像结果显示oHSV1_hTERTp_ICP4CMVp_Luc2在荷BGC823肿瘤裸鼠的肿瘤内能长期存活,而在肌肉和皮下组织内则被迅速清除。(5)在病毒感染端粒酶阴性的Saos-2骨肉瘤细胞后,hTERT mRNA表达上升,说明病毒感染可能会造成hTERT启动子活性上升,然而病毒在该细胞中未能显著复制,以及产生明显的细胞毒作用,从另一方面表明该病毒对端粒酶阴性的正常细胞是安全的。随后我们检测了三个与hTERT启动子活性相关的细胞因子c-myc、Sp1和E2F1在oHSV1_hTERTp_ICP4感染后的表达变化,发现只有E2F1mRNA在病毒感染后较对照组大幅下降,结果暗示其可能与hTERT启动子活性变化有关。(6)端粒酶阳性BGC823细胞在被oHSV1_hTERTp_ICP4感染后坏死细胞比例对凋亡细胞比例的比值随感染剂量的增加而升高,结果提示病毒的细胞毒作用以裂解细胞造成细胞坏死为主。
结论：本研究首次在单纯疱疹病毒中应用hTERT启动子,构建出新型溶瘤单纯疱疹病毒oHSV1_hTERTp_ICP4。该病毒在体内外实验中被证明是一种安全性更好且具有良好溶瘤活性的新型溶瘤单纯疱疹病毒,可以在癌症诊断和治疗中发挥作用。
Background:Oncolytic virotherapy, which uses oncolytic virus such as adenovirus, herpes simplex virus and Newcastle disease virus etc. to kill tumor cells directly, has been proved as a novel and useful strategy for cancer treatment in recent20years. Furthermore, tumor-specific replication-selective oncolytic virotherapy, which uses the virus that can induce cell death in tumor cells but not in normal cells, is a promising and safe way to treat cancer. For now, toxicity is a major obstacle in application of oncolytic virus. In order to solve this problem, based on oHSV1-17+, we have constructed a new oncolytic herpes simplex virus, oHSVl_hTERTp_ICP4, which is anticipated to selectively replicate in most cancer cells but not in normal somatic cells by using a tumor specific promoter to control ICP4that is critical for the transcriptional activation and replication of the virus. Here we evaluated the antitumor effect and tumor specificity of oHSV1_hTERTp_ICP4on series of tumor cells, in vitro and in vivo.
Method:3recombinant oncolytic virus, oHSV1_hTERTp_ICP4, oHSV1_hTERTp_ICP4_CMVp_eGFP and oHSV1_hTERTp_ICP4_CMVp_Luc2, were constructed using plasmid construction and homologous recombination. In vitro cytopathic efficacy of oHSV1_hTERTp_ICP4was examined in several cell lines; and In vitro replication of oHSV1_hTERTp_ICP4in several cell lines was examined using titer determination; and cytopathic efficacy of oHSV1_hTERTp_ICP4for normal human blood cells was examined by using flow cytometry and confocol; and antitumor effects of oHSV1_hTERTp_ICP4were assessed in xenograft tumor models and in vivo imaging; and the effect of oHSV1_hTERTp_ICP4infection on the activity of hTERT promoter and mRNA expression of several transcription factors which may be invovled were identified by Quantitative real-time PCR; finally, the relationship between the cytopathic effect of oHSVl_hTERTp_ICP4and cell necrosis and apoptosis was examined.
Results:(1) oHSV1_hTERTp_ICP4, oHSV1_hTERTp_ICP4_CMVp_eGFP and oHSVl_hTERTp_ICP4_CMVp_Luc2were constructed for the first time.(2) oHSVl_hTERTp_ICP4was cytopathic for most telomerase high activity cell lines with and achieved a similar oncolytic effect compared to oHSV1_17+; but for some cell lines which show no or very low telomerase activity, oHSV1hTERTp ICP4showed no cytopathic effect, while oHSVl-17+was still cytopathic. On the other hand, and the consistency between cytopathic effect and replication of oHSV1_hTERTp_ICP4was clear and definite.(3) The results of flow cytometric analysis showed there were almost no green fluorescent cells found after infection of normal human blood cells with oHSV1_hTERTp_ICP4_CMVp_eGFP, while a small amount of green fluorescent cells were found after infection of oHSV1-17+-GFP. The results suggest that oHSV1_hTERTp_ICP4is much safer than oHSV1-17+. On the other hand, we simulated circulating tumor cells in cancer patients by incorporating Huh-7cells into normal human blood cells, and after infection of oHSV1_hTERTp_ICP4_CMVp_eGFP, the consistant expression of EpCAM and GFP showed the tumor specificity of oHSV1_hTERTp_ICP4again.(4) Antitumor effect of oHSV1_hTERTp_ICP4against BGC823xenograft tumor models was similar to that of oHSV1-17+, but the survival of the mice treated with oHSV1_hTERTp_ICP4were much longer compared to that treated with oHSV1-17+. On the other hand, there was a persistent replication of oHSVl_hTERTp_ICP4_CMVp_Luc2found in tumor, but the viruses in muscle and subcutaneous tissue were eliminated rapidly.(5) The upregulation of hTERT mRNA expression after infection of oHSV1_hTERTp_ICP4indicated the enhanced activity of hTERT promoter which may induce the replication of oHSV1_hTERTp_ICP4, but the former result showed that there were no significant virus replication and cytopathic effect. Furthermore, the mRNA expression of3cellular transcription factors(c-myc, Spl and E2F1) were identified. The results showed that E2F1mRNA expression is downregualted and indicated E2F1may be involved in regulation of hTERT promoter activity that was infected with oHSV1_hTERTp_ICP4.(6) In BGC823cells infected with different MOI of oHSV1_hTERTp_ICP4, the proportion of necrotic cells to proportion of apoptotic cells ratio increased in a MOI-dependent manner, and this result indicated that the cytopathic effect of oHSV1_hTERTp_ICP4is mainly caused by cell lysis and accompanying necrosis.
Conclusions:For the first time, a novol oncolytic virus, oHSV1_hTERTp_ICP4, was constructed with the application of hTERT promoter. A better saftey oncolytic activity was proved in in vitro and in vivo experiments, and indicated that oHSV1_hTERTp_ICP4could be a powerful tool in cancer diagnosis and treatment.
方法：本研究主要通过质粒构建和同源重组技术完成重组新病毒oHSV1_hTERTp_ICP4和两种具有示踪作用的病毒oHSV1_hTERTp_ICP4_CMVp_eGFP和oHSV1_hTERTp_ICP4_CMVp_Luc2的构建工作；通过CCK-8细胞增殖实验检测oHSV1_hTERTp_ICP4对多种肿瘤和正常细胞系的杀伤能力；通过滴度测定方法检测oHSV1_hTERTp_ICP4在多种细胞系中的增殖情况；通过流式细胞术和激光共聚焦技术明确oHSV1_hTERTp_ICP4对正常人血细胞的感染复制情况；通过动物实验初步评价oHSV1_hTERTp_ICP4在BGC823肿瘤模型中的抗肿瘤效果,并使用oHSV1_hTERTp_ICP4_CMVp_Luc2示踪检测新病毒在荷瘤裸鼠中不同组织内的复制表达情况；通过实时定量PCR实验检测oHSV1_hTERTp_ICP4感染细胞后对hTERT启动子活性的影响；最后通过AnnexinV+PI双染法检测oHSV1_hTERTp_ICP4的细胞毒作用与细胞坏死和凋亡间的关系。
结果：(1)本研究成功构建了含有hTERT启动子的新病毒oHSV1_hTERTp_ICP4及具有示踪作用的病毒oHSV1_hTERTp_ICP4_CMVp_eGFP和oHSV1_hTERTp_ICP4_CMVp_Luc2。(2) oHSV1_hTERTp_ICP4在端粒酶阳性肿瘤细胞系中显示出与原病毒oHSV1-17+相似的溶瘤活性；并且在端粒酶阴性细胞系中,没有造成明显的损伤(正常剂量MOI=0.1,1),而oHSV1-17+却显示出了明显的杀伤作用。另外,我们发现oHSV1_hTERTp_ICP4在多种细胞中的增殖能力和细胞毒作用具有一致性。(3)经流式检测,在正常人血细胞中oHSV1-17+-GFP感染后出现了少量的绿色荧光细胞,而oHSV1_hTERTp_ICP4_CMVp_eGFP感染后几乎没有绿色荧光细胞被发现；另外,激光共聚焦结果显示新病毒只在掺杂入的肿瘤细胞中显著增殖,而在正常细胞中未发生显著增殖,以上结果表明新病毒在正常人血细胞中具有良好的安全性。(4)在荷BGC823肿瘤裸鼠模型中,oHSV1_hTERTp_ICP4显示出了与oHSV1-17+相似的抑瘤效果,但在生存期上却明显优于后者；小鼠活体成像结果显示oHSV1_hTERTp_ICP4CMVp_Luc2在荷BGC823肿瘤裸鼠的肿瘤内能长期存活,而在肌肉和皮下组织内则被迅速清除。(5)在病毒感染端粒酶阴性的Saos-2骨肉瘤细胞后,hTERT mRNA表达上升,说明病毒感染可能会造成hTERT启动子活性上升,然而病毒在该细胞中未能显著复制,以及产生明显的细胞毒作用,从另一方面表明该病毒对端粒酶阴性的正常细胞是安全的。随后我们检测了三个与hTERT启动子活性相关的细胞因子c-myc、Sp1和E2F1在oHSV1_hTERTp_ICP4感染后的表达变化,发现只有E2F1mRNA在病毒感染后较对照组大幅下降,结果暗示其可能与hTERT启动子活性变化有关。(6)端粒酶阳性BGC823细胞在被oHSV1_hTERTp_ICP4感染后坏死细胞比例对凋亡细胞比例的比值随感染剂量的增加而升高,结果提示病毒的细胞毒作用以裂解细胞造成细胞坏死为主。
结论：本研究首次在单纯疱疹病毒中应用hTERT启动子,构建出新型溶瘤单纯疱疹病毒oHSV1_hTERTp_ICP4。该病毒在体内外实验中被证明是一种安全性更好且具有良好溶瘤活性的新型溶瘤单纯疱疹病毒,可以在癌症诊断和治疗中发挥作用。
Background:Oncolytic virotherapy, which uses oncolytic virus such as adenovirus, herpes simplex virus and Newcastle disease virus etc. to kill tumor cells directly, has been proved as a novel and useful strategy for cancer treatment in recent20years. Furthermore, tumor-specific replication-selective oncolytic virotherapy, which uses the virus that can induce cell death in tumor cells but not in normal cells, is a promising and safe way to treat cancer. For now, toxicity is a major obstacle in application of oncolytic virus. In order to solve this problem, based on oHSV1-17+, we have constructed a new oncolytic herpes simplex virus, oHSVl_hTERTp_ICP4, which is anticipated to selectively replicate in most cancer cells but not in normal somatic cells by using a tumor specific promoter to control ICP4that is critical for the transcriptional activation and replication of the virus. Here we evaluated the antitumor effect and tumor specificity of oHSV1_hTERTp_ICP4on series of tumor cells, in vitro and in vivo.
Method:3recombinant oncolytic virus, oHSV1_hTERTp_ICP4, oHSV1_hTERTp_ICP4_CMVp_eGFP and oHSV1_hTERTp_ICP4_CMVp_Luc2, were constructed using plasmid construction and homologous recombination. In vitro cytopathic efficacy of oHSV1_hTERTp_ICP4was examined in several cell lines; and In vitro replication of oHSV1_hTERTp_ICP4in several cell lines was examined using titer determination; and cytopathic efficacy of oHSV1_hTERTp_ICP4for normal human blood cells was examined by using flow cytometry and confocol; and antitumor effects of oHSV1_hTERTp_ICP4were assessed in xenograft tumor models and in vivo imaging; and the effect of oHSV1_hTERTp_ICP4infection on the activity of hTERT promoter and mRNA expression of several transcription factors which may be invovled were identified by Quantitative real-time PCR; finally, the relationship between the cytopathic effect of oHSVl_hTERTp_ICP4and cell necrosis and apoptosis was examined.
Results:(1) oHSV1_hTERTp_ICP4, oHSV1_hTERTp_ICP4_CMVp_eGFP and oHSVl_hTERTp_ICP4_CMVp_Luc2were constructed for the first time.(2) oHSVl_hTERTp_ICP4was cytopathic for most telomerase high activity cell lines with and achieved a similar oncolytic effect compared to oHSV1_17+; but for some cell lines which show no or very low telomerase activity, oHSV1hTERTp ICP4showed no cytopathic effect, while oHSVl-17+was still cytopathic. On the other hand, and the consistency between cytopathic effect and replication of oHSV1_hTERTp_ICP4was clear and definite.(3) The results of flow cytometric analysis showed there were almost no green fluorescent cells found after infection of normal human blood cells with oHSV1_hTERTp_ICP4_CMVp_eGFP, while a small amount of green fluorescent cells were found after infection of oHSV1-17+-GFP. The results suggest that oHSV1_hTERTp_ICP4is much safer than oHSV1-17+. On the other hand, we simulated circulating tumor cells in cancer patients by incorporating Huh-7cells into normal human blood cells, and after infection of oHSV1_hTERTp_ICP4_CMVp_eGFP, the consistant expression of EpCAM and GFP showed the tumor specificity of oHSV1_hTERTp_ICP4again.(4) Antitumor effect of oHSV1_hTERTp_ICP4against BGC823xenograft tumor models was similar to that of oHSV1-17+, but the survival of the mice treated with oHSV1_hTERTp_ICP4were much longer compared to that treated with oHSV1-17+. On the other hand, there was a persistent replication of oHSVl_hTERTp_ICP4_CMVp_Luc2found in tumor, but the viruses in muscle and subcutaneous tissue were eliminated rapidly.(5) The upregulation of hTERT mRNA expression after infection of oHSV1_hTERTp_ICP4indicated the enhanced activity of hTERT promoter which may induce the replication of oHSV1_hTERTp_ICP4, but the former result showed that there were no significant virus replication and cytopathic effect. Furthermore, the mRNA expression of3cellular transcription factors(c-myc, Spl and E2F1) were identified. The results showed that E2F1mRNA expression is downregualted and indicated E2F1may be involved in regulation of hTERT promoter activity that was infected with oHSV1_hTERTp_ICP4.(6) In BGC823cells infected with different MOI of oHSV1_hTERTp_ICP4, the proportion of necrotic cells to proportion of apoptotic cells ratio increased in a MOI-dependent manner, and this result indicated that the cytopathic effect of oHSV1_hTERTp_ICP4is mainly caused by cell lysis and accompanying necrosis.
Conclusions:For the first time, a novol oncolytic virus, oHSV1_hTERTp_ICP4, was constructed with the application of hTERT promoter. A better saftey oncolytic activity was proved in in vitro and in vivo experiments, and indicated that oHSV1_hTERTp_ICP4could be a powerful tool in cancer diagnosis and treatment.
引文
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