NDV HN基因和CAV Apoptin基因对宫颈癌细胞的体外杀伤作用及其体内抑瘤效应研究
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摘要
本研究以新城疫病毒(NDV)血凝素-神经氨酸酶(HN)基因和鸡贫血病毒(CAV)凋亡素(Apoptin)基因为效应基因,以真核表达质粒pSFV为载体,分别构建了含HN和Apoptin基因的重组真核表达质粒pSFVHN、pSFVApoptin。利用以鸡痘病毒为载体的重组鸡痘病毒vFVHN、vFVApoptin及上述重组真核表达质粒对其进行了体内外抑瘤实验研究和抑瘤机制的初步探索,为上述两种基因在肿瘤生物治疗中的应用奠定实验和理论基础。
本研究以真核表达质粒pSFV为载体,分别构建了能够有效表达NDVHN和CAV Apoptin的重组真核表达质粒pSFVHN和pSFVApoptin。通过电穿孔法将pSFVHN和pSFVApoptin转染入人宫颈癌Hela细胞通过RT-PCR、western-blot法及间接免疫荧光检测了重组体中外源基因在Hela细胞内表达,结果表明外源基因Apoptin和HN在Hela细胞中获得了有效转录和正确表达;采用MTT法分别检测了pSFVHN和pSFVApoptin对Hela肿瘤细胞的体外杀伤作用,结果表明,上述重组体对Hela细胞具有明显的杀伤作用;通过吖锭橙/溴化乙锭染色、DAPI染色、流式细胞仪结合DCFA染色、罗丹明123染色分别探讨了两种重组体对Hela肿瘤细胞的抑制机制,结果表明,pSFVHN和pSFVApoptin可诱导Hela肿瘤细胞凋亡,并可上调细胞内活性氧水平,降低线粒体膜电位,由此推测其所诱导的细胞凋亡可能是通过线粒体途径发生的;通过流式细胞仪结合MHC-Ⅰ分子表达检测等方法检测了两种重组体对细胞免疫功能的影响,结果表明,pSFVHN和pSFVApoptin可不同程度的上调肿瘤细胞表面MHC-Ⅰ分子的表达,提高肿瘤细胞的免疫原性。
本研究利用重组鸡痘病毒vFVHN和vFVApoptin感染体外培养的人宫颈癌Hela细胞,运用Western blot、RT-PCR和间接免疫荧光等方法检测外源基因的表达,实验结果显示,重组鸡痘病毒所携带的外源基因可在Hela细胞中有效转录和正确表达。采用MTT法、吖锭橙/溴化乙锭染色、DAPI染色、流式细胞仪检测细胞内活性氧水平、线粒体膜电位及MHC-Ⅰ分子的表达等方法观察重组鸡痘病毒vFVHN和vFVApoptin对Hela肿瘤细胞的体外杀伤作用及其对肿瘤细胞免疫原性的影响,实验结果显示,上述重组病毒可有效抑制Hela细胞的生长,并可推测其可通过线粒体途径诱导人宫颈癌Hela细胞发生凋亡。
另外,其次本研究还复制了C57BL/6小鼠荷H22肿瘤模型,利用瘤内注射的方法,通过抑瘤率检测和生存期检测等方法探讨了重组真核表达质粒pSFVHN、pSFVApoptin和重组鸡痘病毒vFVHN和vFVApoptin的体内抑瘤作用。结果显示,上述重组体可有效抑制荷瘤动物模型肿瘤组织的生长,并在一定程度上延长动物模型生存期。本研究还通过小鼠脾CD4+、CD8+T细胞亚群的数量、脾细胞特异性CTL杀伤活性等检测,探讨了上述重组体对荷瘤动物模型免疫功能的影响,结果显示,上述重组体可在不同程度内提高荷瘤动物模型CD4+、CD8+T细胞亚群的数量,并诱导产生抗肿瘤特异性CTL杀伤活性。
本研究通过对重组真核表达质粒pSFVHN、pSFVApoptin和重组鸡痘病毒vFVHN和vFVApoptin的体内外抑瘤作用研究,说明了其对体外培养的人宫颈癌Hela细胞和C57BL/6小鼠荷H22肿瘤模型的抑制作用。提示,NDV HN和CAV Apoptin可作为效应基因应用于肿瘤生物治疗领域,但对其确切机制尚需进一步研究。
Cancer constitutes one of the most important medico-biological problems remaining generally unsolved at the beginning of the new century. Although involvement of numerous genetic factors in the pathogenesis of neoplasia is well proven, understanding of the complex molecular mechanisms underlying neoplastic growth is still disappointingly incomplete. Intense investigation of cancer-related genetic alterations at the somatic cell level has shed some light on the sequence of molecular events leading to malignant transformation of somatic cells and clonal neoplastic growth. It is now believed that most (and probably all) types of cancer share a relatively small number of molecular, biochemical and cellular traits called acquired capabilities. As that following six alterations relevant for malignancy: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. Indeed, neoplastic growth should not be regarded as a cell-autonomous process intrinsic to the cancer cell. There is no doubt that cancer development strongly depends upon changes in interactions between malignant cells and their normal neighbours. For many cancers, conventional therapies render patients free of disease but relapse and death remains high, particularly in advanced cancers. Thus, there is great interesting developing novel therapies that can completely remove residual disease and prolong life. Although many novel approaches have been advanced in recent years, interest in cancer gene therapy has been exceptionally strong. The development of genetically engineer viruses and viral proteins that selectively target various tumors resulting in minimal toxicity in the normal tissues has emerged as a potentially important approach for cancer gene therapy.
To investigate the mechanisms of effect on human cervical carcinoma cells Hela with Hemagglutinin-neuraminidase from Newcastle disease virus and Apoptin from from chicken anemia virus. We constructed recombinant plasmid pSFVHN and pSFVApoptin. The above recombinant expression plasmid was identified by enzyme and transfected into human cervical carcinoma Hela cells, then the recombinant was screened by using RT-PCR, western-blot and indirect immunofluorescence. The results showed that the apoptin gene and HN gene transcribed and expressed correctly in Hela cells. Hela cells were transfected with pSFVHN and pSFVApoptin and the anti-tumor effects in vitro were observed by using microscope. The results showed that the recombinants has evident lethal effects on Hela cells and the effects showed non-limit time-dose dependent relationship. The lethal effects were reinforced with the growth of transfection time and the concentration of the recombinant. The peak was reached 48 hours after infection when the concentration of the recombinant was 20μg/ml, the value is 59.3%和51.5%. AO/EB staining and DAPI staining were used to observe the cell morphological diversity, the results showed that pSFVHN and pSFVApoptin lead to the cell pyknosis, chromatin margination and apoptosis finally. DCFA staining to detect the Reactive oxygen species level, Rhodamine123 staining to detect the mitochondrial trans-memebrane potential and anti-MHC-I Mab coherent to detect the MHC-I level were used to observe the mechanism of anti-tumor effect of pSFVHN and pSFVApoptin and meanings of the pSFVHN and pSFVApoptin in activating immune. The results showed that the recombinant caused the decline of mitochondrial trans-membrane potential and step up of Reactive oxygen species level. In conclusion, the transfection of pSFVHN and pSFVApoptin ultimately induced Hela cell apoptosis and the apoptosis induce by the recombination is mainly through mitochondrial pathway.
To observe the therapeutic alliance effects of apoptin gene and HN gene, Hela cells were infected by recombinant fowlpox virus vFVApoptin and vFVHN. RT-PCR, Western blot and indirect immunofluorescence was used to identify the expression of vFVApoptin and vFVHN. The results showed that the recombinant transcribed and expressed foreign protein magnanimously. MTT assay was used to detect the anti-tumor effects of vFVApoptin and vFVHN on Hela cells. The results showed that the recombinant can kill the tumor cells effectively as described below: 65.9%和55.8%. AO/EB and DAPI staining was used to observe the cell morphological diversity, the results showed that the recombinant fowlpox viruses lead to the cell pyknosis, chromatin margination and apoptosis finally. DCFA staining to detect the Reactive oxygen species level, Rhodamine123 staining to detect the mitochondrial trans-memebrane potential were used to observe the mechanism of anti-tumor effect of vFVApoptin and vFVHN. The results showed that the recombinant caused the decline of mitochondrial trans-membrane potential and step up of Reactive oxygen species level. In conclusion, the transfection of vFVApoptin and vFVHN ultimately induced Hela cell apoptosis and the apoptosis induce by the recombination is mainly through mitochondrial pathway. On the other hand, we applied FCM to detect the level of MHC-I, The results showed that the recombinant fowlpox viruses lead to up-regulation of MHC-I molecule.
Furthermore, C57BL/6 mice model bearing H22 hepatoma was constructed by transplanting H22 cells into the right hind limb of the mice and the combined or single anti-tumor effect on H22 hepatoma of HN gene and apoptin gene was observed through the detection of anti-tumor ratio, survival rate, categorization of subset of splenic lymphocyte, CTL activity and the immuneostimulation. The results showed that that the growth of established tumors in mice immunized with the recombinants was significantly inhibited and the survival rate was prolonged. Furthermore, the immunization of mice with the recombinants elicited strong tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro. In addition, CD4~+、CD8~+ T cells from mice vaccinated with the recombinants were elevated. Indicating that vaccination with the recombinants may be a novel and powerful strategy for cancer bio-therapy and the precise mechanism is on going investigation.
本研究以真核表达质粒pSFV为载体,分别构建了能够有效表达NDVHN和CAV Apoptin的重组真核表达质粒pSFVHN和pSFVApoptin。通过电穿孔法将pSFVHN和pSFVApoptin转染入人宫颈癌Hela细胞通过RT-PCR、western-blot法及间接免疫荧光检测了重组体中外源基因在Hela细胞内表达,结果表明外源基因Apoptin和HN在Hela细胞中获得了有效转录和正确表达;采用MTT法分别检测了pSFVHN和pSFVApoptin对Hela肿瘤细胞的体外杀伤作用,结果表明,上述重组体对Hela细胞具有明显的杀伤作用;通过吖锭橙/溴化乙锭染色、DAPI染色、流式细胞仪结合DCFA染色、罗丹明123染色分别探讨了两种重组体对Hela肿瘤细胞的抑制机制,结果表明,pSFVHN和pSFVApoptin可诱导Hela肿瘤细胞凋亡,并可上调细胞内活性氧水平,降低线粒体膜电位,由此推测其所诱导的细胞凋亡可能是通过线粒体途径发生的;通过流式细胞仪结合MHC-Ⅰ分子表达检测等方法检测了两种重组体对细胞免疫功能的影响,结果表明,pSFVHN和pSFVApoptin可不同程度的上调肿瘤细胞表面MHC-Ⅰ分子的表达,提高肿瘤细胞的免疫原性。
本研究利用重组鸡痘病毒vFVHN和vFVApoptin感染体外培养的人宫颈癌Hela细胞,运用Western blot、RT-PCR和间接免疫荧光等方法检测外源基因的表达,实验结果显示,重组鸡痘病毒所携带的外源基因可在Hela细胞中有效转录和正确表达。采用MTT法、吖锭橙/溴化乙锭染色、DAPI染色、流式细胞仪检测细胞内活性氧水平、线粒体膜电位及MHC-Ⅰ分子的表达等方法观察重组鸡痘病毒vFVHN和vFVApoptin对Hela肿瘤细胞的体外杀伤作用及其对肿瘤细胞免疫原性的影响,实验结果显示,上述重组病毒可有效抑制Hela细胞的生长,并可推测其可通过线粒体途径诱导人宫颈癌Hela细胞发生凋亡。
另外,其次本研究还复制了C57BL/6小鼠荷H22肿瘤模型,利用瘤内注射的方法,通过抑瘤率检测和生存期检测等方法探讨了重组真核表达质粒pSFVHN、pSFVApoptin和重组鸡痘病毒vFVHN和vFVApoptin的体内抑瘤作用。结果显示,上述重组体可有效抑制荷瘤动物模型肿瘤组织的生长,并在一定程度上延长动物模型生存期。本研究还通过小鼠脾CD4+、CD8+T细胞亚群的数量、脾细胞特异性CTL杀伤活性等检测,探讨了上述重组体对荷瘤动物模型免疫功能的影响,结果显示,上述重组体可在不同程度内提高荷瘤动物模型CD4+、CD8+T细胞亚群的数量,并诱导产生抗肿瘤特异性CTL杀伤活性。
本研究通过对重组真核表达质粒pSFVHN、pSFVApoptin和重组鸡痘病毒vFVHN和vFVApoptin的体内外抑瘤作用研究,说明了其对体外培养的人宫颈癌Hela细胞和C57BL/6小鼠荷H22肿瘤模型的抑制作用。提示,NDV HN和CAV Apoptin可作为效应基因应用于肿瘤生物治疗领域,但对其确切机制尚需进一步研究。
Cancer constitutes one of the most important medico-biological problems remaining generally unsolved at the beginning of the new century. Although involvement of numerous genetic factors in the pathogenesis of neoplasia is well proven, understanding of the complex molecular mechanisms underlying neoplastic growth is still disappointingly incomplete. Intense investigation of cancer-related genetic alterations at the somatic cell level has shed some light on the sequence of molecular events leading to malignant transformation of somatic cells and clonal neoplastic growth. It is now believed that most (and probably all) types of cancer share a relatively small number of molecular, biochemical and cellular traits called acquired capabilities. As that following six alterations relevant for malignancy: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. Indeed, neoplastic growth should not be regarded as a cell-autonomous process intrinsic to the cancer cell. There is no doubt that cancer development strongly depends upon changes in interactions between malignant cells and their normal neighbours. For many cancers, conventional therapies render patients free of disease but relapse and death remains high, particularly in advanced cancers. Thus, there is great interesting developing novel therapies that can completely remove residual disease and prolong life. Although many novel approaches have been advanced in recent years, interest in cancer gene therapy has been exceptionally strong. The development of genetically engineer viruses and viral proteins that selectively target various tumors resulting in minimal toxicity in the normal tissues has emerged as a potentially important approach for cancer gene therapy.
To investigate the mechanisms of effect on human cervical carcinoma cells Hela with Hemagglutinin-neuraminidase from Newcastle disease virus and Apoptin from from chicken anemia virus. We constructed recombinant plasmid pSFVHN and pSFVApoptin. The above recombinant expression plasmid was identified by enzyme and transfected into human cervical carcinoma Hela cells, then the recombinant was screened by using RT-PCR, western-blot and indirect immunofluorescence. The results showed that the apoptin gene and HN gene transcribed and expressed correctly in Hela cells. Hela cells were transfected with pSFVHN and pSFVApoptin and the anti-tumor effects in vitro were observed by using microscope. The results showed that the recombinants has evident lethal effects on Hela cells and the effects showed non-limit time-dose dependent relationship. The lethal effects were reinforced with the growth of transfection time and the concentration of the recombinant. The peak was reached 48 hours after infection when the concentration of the recombinant was 20μg/ml, the value is 59.3%和51.5%. AO/EB staining and DAPI staining were used to observe the cell morphological diversity, the results showed that pSFVHN and pSFVApoptin lead to the cell pyknosis, chromatin margination and apoptosis finally. DCFA staining to detect the Reactive oxygen species level, Rhodamine123 staining to detect the mitochondrial trans-memebrane potential and anti-MHC-I Mab coherent to detect the MHC-I level were used to observe the mechanism of anti-tumor effect of pSFVHN and pSFVApoptin and meanings of the pSFVHN and pSFVApoptin in activating immune. The results showed that the recombinant caused the decline of mitochondrial trans-membrane potential and step up of Reactive oxygen species level. In conclusion, the transfection of pSFVHN and pSFVApoptin ultimately induced Hela cell apoptosis and the apoptosis induce by the recombination is mainly through mitochondrial pathway.
To observe the therapeutic alliance effects of apoptin gene and HN gene, Hela cells were infected by recombinant fowlpox virus vFVApoptin and vFVHN. RT-PCR, Western blot and indirect immunofluorescence was used to identify the expression of vFVApoptin and vFVHN. The results showed that the recombinant transcribed and expressed foreign protein magnanimously. MTT assay was used to detect the anti-tumor effects of vFVApoptin and vFVHN on Hela cells. The results showed that the recombinant can kill the tumor cells effectively as described below: 65.9%和55.8%. AO/EB and DAPI staining was used to observe the cell morphological diversity, the results showed that the recombinant fowlpox viruses lead to the cell pyknosis, chromatin margination and apoptosis finally. DCFA staining to detect the Reactive oxygen species level, Rhodamine123 staining to detect the mitochondrial trans-memebrane potential were used to observe the mechanism of anti-tumor effect of vFVApoptin and vFVHN. The results showed that the recombinant caused the decline of mitochondrial trans-membrane potential and step up of Reactive oxygen species level. In conclusion, the transfection of vFVApoptin and vFVHN ultimately induced Hela cell apoptosis and the apoptosis induce by the recombination is mainly through mitochondrial pathway. On the other hand, we applied FCM to detect the level of MHC-I, The results showed that the recombinant fowlpox viruses lead to up-regulation of MHC-I molecule.
Furthermore, C57BL/6 mice model bearing H22 hepatoma was constructed by transplanting H22 cells into the right hind limb of the mice and the combined or single anti-tumor effect on H22 hepatoma of HN gene and apoptin gene was observed through the detection of anti-tumor ratio, survival rate, categorization of subset of splenic lymphocyte, CTL activity and the immuneostimulation. The results showed that that the growth of established tumors in mice immunized with the recombinants was significantly inhibited and the survival rate was prolonged. Furthermore, the immunization of mice with the recombinants elicited strong tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro. In addition, CD4~+、CD8~+ T cells from mice vaccinated with the recombinants were elevated. Indicating that vaccination with the recombinants may be a novel and powerful strategy for cancer bio-therapy and the precise mechanism is on going investigation.
引文
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