特异性抗肿瘤重组腺病毒抑癌作用研究
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摘要
为更好的研究重组腺病毒抗肿瘤制剂在临床应用过程中存在的安全性和有效性,本研究利用分子生物学、病毒学和免疫学等技术和手段,通过同源重组方法构建了分别含有特异性抑癌基因HN、Apoptin的特异性抗肿瘤重组腺病毒;同时构建了对照重组腺病毒,Ad-EGFP。通过一系列实验研究证明,所获得重组腺病毒性状稳定,形态完整。
通过MTT染色、AO/EB染色、流式细胞术等方法检测了重组腺病毒感染对HepG-2人肝癌细胞的抑制作用。证明了,Ad-Apoptin和Ad-HN重组腺病毒可不同程度地抑制体外培养的HepG-2肿瘤细胞。利用Annexin V染色、DAPI染色、Caspase活性检测等方法探讨了所构建重组腺病毒致HepG-2细胞死亡的方式。证实了,Ad-Apoptin、Ad-HN重组腺病毒主要以诱导凋亡的方式抑制体外培养的HepG-2肿瘤细胞。
通过在C57BL/6小鼠荷小鼠肝癌(H22)肿瘤模型上的体内实体肿瘤抑制试验,发现Ad-Apoptin、Ad-HN均可不同程度地抑制实体肿瘤的生长,提高荷瘤动物模型生存率,延长荷瘤动物模型生存期。另外,Ad-HN还可以刺激机体产生抗肿瘤免疫效应。
上述研究为揭示HN、Apoptin的抑瘤和免疫调控机理提供了有价值的参考数据。
Tumor is a kind of disease which can threaten human health seriously.Because of its specific biological behaviour,operation,radiotherapy and chemotherapy can not increase survival quality of patients and prolong their life.Yet,many of these deaths can be avoided. Over 40%of all malignant tumours can be prevented.Others can be detected early,treated and cured.Even with late stage cancer,the suffering of patients can be relieved with good palliative care.With the development of molecular biology and hnmunology,we realized that tumor ia a kind of disease related gene,abnormality of normocellular growth control and mutation of apoptosis regulatory gene can result in alteration of function,then tumor cell get the ability of metastasis and infiltration,proliferate minute primary lesion gradually.
In this study,Apoptin and HN gene were placed downstream of CMV promoter of shuttle plasmid of RAPAd.I system.The recombined recombinant adenovirus named Ad-HN and Ad-Apoptin.The above shuttle plasmids of dual specific recombinant adenovirus and genome skeleton of RAPAd.I system were co-transfected into AAV-293 cells.The recombinant adenoviruses Ad-HN,Ad-Apoptin and Ad-EGFP were obtained by homologous recombination.The expression of Apoptin,HN of the recombinant adenovirus was identified by RT-PCR,western blot and indirect immunofluorescence.The results showed that the foreign genes expressed effectively in HepG-2 cells.HN gene has activity of neuraminidase, hydrolyze sialic acid in the surface of tumor cell,expose tumour-cell surface antigen, strengthen identification and killing of tumor cell through immune system.HN can induce IFN,increase recognization of tuor cell by CTL,correct functional defect of immune system partly.Apoptin can induce apoptosis of tumor cell,its function don not depend on p53 and bcl-2,Apoptin can not induce normal cell.
The anti-tumor effects of Ad-Apoptin,Ad-HN and Ad-EGFP on HepG-2 cells were detected by MTT.The results showed that,except for Ad-EGFP,Ad-Apoptin and Ad-HN killed HepG-2 cells in varying degrees.In the certain time frame,the suppression rates of Ad-HN and Ad-Apoptin on HepG-2 cells were heightened with the stepping up of infective dose.In the definition of infection doses,the suppression rates of Ad-HN and Ad-Apoptin on HepG-2 cells were improved with the extending of infection time.By using observation of light microscope,AO/EB staining,DAPI staining,AnnexinⅤstaining and caspase activity detecting,we approached the decease pathway of HepG-2 cells reduced by the dual specific recombinant adenoviruses.The results showed that the recombinant adenovirus induced apoptosis of HepG-2 cells.
C57BL/6 mice model bearing H22 hepatoma was constructed by transplanting H22 hepatoma cell into the right hind limb of the mice and the anti-tumor effects of the recombinant adenoviruses described above were observed through this model.The results showed that,compared with saline and control groups,experiment groups displayed varying degree anti-tumor effects.The suppression rates of Ad-HN(44.65%) and Ad-Apoptin (33.55%),it is higher than that of other groups.
The survival rates of Ad-HN,five of six mice survived(survival rate was 83.33%),was significant higher than saline-,Ad-EGFP-,Ad-Apoptin-treated groups.The survival rates of Ad-Apoptin-treated groups were 50%,and the survival rates of Ad-EGFP- treated groups was 33.33%.The electron microscope observation of tumor cell showed nucleic condensation and localization,chromatin margination,transfected tumor cells showed typical apoptosis.
The results of the.detection of cytokine of Th1/Th2 showed that the recombinant adenovirus up-regulated the level of some cytokines.The level of IL-2 and IFN-γof mice of Ad-HN-treated groups was much higher than other groups.This result illustrated that Ad-HN lead the immune response to Th1 dominant.On the other hand,perhaps,because of the immunostimulation of adenovirus itself,the levels of some cell factors of the mice of Ad-Apoptin-treated groups were up-regulated.
In summary,the dual specific anti-tumor recombinant adenovirus constructed by using RAPAd.I system basing on specific anti-tumor gene Apoptin/HN in the study,which has tumor specific restrain abilities,can suppress HepG-2 cells and prolong life span of animal model effectively.The researches can provide a useful platform for the exploration of more safer,specific,effective anti-tumor medicine.
通过MTT染色、AO/EB染色、流式细胞术等方法检测了重组腺病毒感染对HepG-2人肝癌细胞的抑制作用。证明了,Ad-Apoptin和Ad-HN重组腺病毒可不同程度地抑制体外培养的HepG-2肿瘤细胞。利用Annexin V染色、DAPI染色、Caspase活性检测等方法探讨了所构建重组腺病毒致HepG-2细胞死亡的方式。证实了,Ad-Apoptin、Ad-HN重组腺病毒主要以诱导凋亡的方式抑制体外培养的HepG-2肿瘤细胞。
通过在C57BL/6小鼠荷小鼠肝癌(H22)肿瘤模型上的体内实体肿瘤抑制试验,发现Ad-Apoptin、Ad-HN均可不同程度地抑制实体肿瘤的生长,提高荷瘤动物模型生存率,延长荷瘤动物模型生存期。另外,Ad-HN还可以刺激机体产生抗肿瘤免疫效应。
上述研究为揭示HN、Apoptin的抑瘤和免疫调控机理提供了有价值的参考数据。
Tumor is a kind of disease which can threaten human health seriously.Because of its specific biological behaviour,operation,radiotherapy and chemotherapy can not increase survival quality of patients and prolong their life.Yet,many of these deaths can be avoided. Over 40%of all malignant tumours can be prevented.Others can be detected early,treated and cured.Even with late stage cancer,the suffering of patients can be relieved with good palliative care.With the development of molecular biology and hnmunology,we realized that tumor ia a kind of disease related gene,abnormality of normocellular growth control and mutation of apoptosis regulatory gene can result in alteration of function,then tumor cell get the ability of metastasis and infiltration,proliferate minute primary lesion gradually.
In this study,Apoptin and HN gene were placed downstream of CMV promoter of shuttle plasmid of RAPAd.I system.The recombined recombinant adenovirus named Ad-HN and Ad-Apoptin.The above shuttle plasmids of dual specific recombinant adenovirus and genome skeleton of RAPAd.I system were co-transfected into AAV-293 cells.The recombinant adenoviruses Ad-HN,Ad-Apoptin and Ad-EGFP were obtained by homologous recombination.The expression of Apoptin,HN of the recombinant adenovirus was identified by RT-PCR,western blot and indirect immunofluorescence.The results showed that the foreign genes expressed effectively in HepG-2 cells.HN gene has activity of neuraminidase, hydrolyze sialic acid in the surface of tumor cell,expose tumour-cell surface antigen, strengthen identification and killing of tumor cell through immune system.HN can induce IFN,increase recognization of tuor cell by CTL,correct functional defect of immune system partly.Apoptin can induce apoptosis of tumor cell,its function don not depend on p53 and bcl-2,Apoptin can not induce normal cell.
The anti-tumor effects of Ad-Apoptin,Ad-HN and Ad-EGFP on HepG-2 cells were detected by MTT.The results showed that,except for Ad-EGFP,Ad-Apoptin and Ad-HN killed HepG-2 cells in varying degrees.In the certain time frame,the suppression rates of Ad-HN and Ad-Apoptin on HepG-2 cells were heightened with the stepping up of infective dose.In the definition of infection doses,the suppression rates of Ad-HN and Ad-Apoptin on HepG-2 cells were improved with the extending of infection time.By using observation of light microscope,AO/EB staining,DAPI staining,AnnexinⅤstaining and caspase activity detecting,we approached the decease pathway of HepG-2 cells reduced by the dual specific recombinant adenoviruses.The results showed that the recombinant adenovirus induced apoptosis of HepG-2 cells.
C57BL/6 mice model bearing H22 hepatoma was constructed by transplanting H22 hepatoma cell into the right hind limb of the mice and the anti-tumor effects of the recombinant adenoviruses described above were observed through this model.The results showed that,compared with saline and control groups,experiment groups displayed varying degree anti-tumor effects.The suppression rates of Ad-HN(44.65%) and Ad-Apoptin (33.55%),it is higher than that of other groups.
The survival rates of Ad-HN,five of six mice survived(survival rate was 83.33%),was significant higher than saline-,Ad-EGFP-,Ad-Apoptin-treated groups.The survival rates of Ad-Apoptin-treated groups were 50%,and the survival rates of Ad-EGFP- treated groups was 33.33%.The electron microscope observation of tumor cell showed nucleic condensation and localization,chromatin margination,transfected tumor cells showed typical apoptosis.
The results of the.detection of cytokine of Th1/Th2 showed that the recombinant adenovirus up-regulated the level of some cytokines.The level of IL-2 and IFN-γof mice of Ad-HN-treated groups was much higher than other groups.This result illustrated that Ad-HN lead the immune response to Th1 dominant.On the other hand,perhaps,because of the immunostimulation of adenovirus itself,the levels of some cell factors of the mice of Ad-Apoptin-treated groups were up-regulated.
In summary,the dual specific anti-tumor recombinant adenovirus constructed by using RAPAd.I system basing on specific anti-tumor gene Apoptin/HN in the study,which has tumor specific restrain abilities,can suppress HepG-2 cells and prolong life span of animal model effectively.The researches can provide a useful platform for the exploration of more safer,specific,effective anti-tumor medicine.
引文
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