减毒沙门氏菌携带共表达siRNA-mdm2与p53质粒抗前列腺癌的实验研究
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摘要
目的:探讨共表达siRNA-mdm2与p53质粒对前列腺癌细胞株PC-3的联合效应及用减毒沙门氏菌携带共表达siRNA-mdm2与p53质粒增强对裸鼠前列腺癌移植瘤的治疗作用,为前列腺癌的基因治疗提供新的实验依据。
方法:免疫组化技术检测人正常前列腺组织和前列腺癌组织mdm2和p53的表达;基因重组技术构建共表达siRNA-mdm2与p53质粒;真核细胞转染技术将共表达质粒转入前列腺癌PC-3细胞;MTT法检测共表达质粒对PC-3细胞增殖活性的影响;流式细胞术检测共表达质粒对PC-3细胞凋亡的影响;半定量RT-PCR和Western blot检测共表达质粒对mdm2和p53及其相关基因的表达;应用减毒沙门氏菌(Ty21a)携带共表达siRNA-mdm2与p53质粒治疗裸鼠前列腺癌移植瘤,观察其对移植瘤生长的影响。
结果:免疫组化检测到人前列腺癌组织中mdm2和mt-p53高表达,与正常前列腺组织表达有显著差异性,两者呈正相关;基因重组技术成功构建了共表达siRNA-mdm2与p53质粒;MTT检测到共表达质粒对PC-3细胞有抑制增殖作用;流式细胞术检测到共表达质粒对PC-3细胞有促进凋亡作用;透射电镜观察到共表达质粒治疗组肿瘤细胞核固缩等形态学变化;半定量RT-PCR和Western blot检测到共表达质粒促进了P21的表达,而CDK4,cyclin-D1, HIF-1α,pRb,E2F-1的表达被抑制;减毒沙门氏菌携带的共表达siRNA-mdm2与p53质粒明显增强抑制了裸鼠前列腺癌移植瘤的生长;减毒沙门氏菌作为siRNA-mdm2与p53共表达质粒的运载体,起到了靶向性治疗作用。
结论:共表达siRNA-mdm2与p53质粒抑制了前列腺癌细胞PC-3的增殖;减毒沙门氏菌携带共表达siRNA-mdm2与p53质粒对裸鼠前列腺癌移植瘤具有显著的治疗作用。本研究首次构建了共表达siRNA-mdm2与p53质粒,并用减毒沙门氏菌人用疫苗株携带共表达质粒治疗裸鼠前列腺癌移植瘤,为临床肿瘤多基因联合治疗奠定实验基础。
Prostate cancer is the most common cancer in American men. Recently the incidence rate of prostate cancer has increased rapidly in China. Men currently diagnosed at the early stages of prostate cancer can, in many cases, be effectively treated by surgery or radiation. However, in one third of the patients, the disease will recur and ultimately develop into hormone-refractory prostate cancer and metastatic prostate cancers that are essentially incurable. As a new treatment of tumor gene therapy is thought highly of increasingly.
P53 gene is an important tumor suppressor gene, which by preventing cell replication and promoting apoptosis to maintain genomic stability, the maintenance of normal cell growth, and inhibit the proliferation of malignant cells, and be a negative effect on growth regulation. Its mutation and inactivation plays an important role in the process in tumor growth in and infiltration. P53 inactivation showed over-expression of mutant p53. Mutant p53 protein not only showed the loss of the normal tumor suppressor role, but also promoted normal cells to the malignant transformation. It showed that p53 gene mutations may be closely related to a variety of human tumors. In lung cancer, colon cancer, breast cancer, liver cancer, prostate cancer, bladder cancer, ovarian cancer, brain tumor, nasopharyngeal carcinoma, there are reports of high expression of p53. It is reported that nearly half of prostate cancer positive for mutant p53 expression, p53 mutation or deletion is closely related with prostate cancer invasion, metastasis and prognosis.
Mouse double minutes -2 gene (mdm2) is an proto-oncogene. mdm2 gene transcription as a p53 target gene can be induced by wild-type p53 to enhance transcription, and the expression of mdm2 protein product can in turn format the complex product with tumor suppressor gene p53 protein by blocking its transcriptional activity, exporting of p53 protein into the cytoplasm and by promoting the degradation of the p53 protein .At the same time, it can stable the mutant p53 protein, thereby blocking the cell growth inhibition of p53. Both of them format p53 / mdm2 negative feedback loop regulation, so that cells of p53 / mdm2 ratio remained constant in order to ensure normal growth of cells. The most important role of mdm2 in vivo is to inhibiting the transcription and anti-tumor activity of wild-type p53 protein. Researches have shown that the abnormity of mdm2-p53 self-regulating loop, not only plays an important role in tumor occurrence and development, but also is closely related to the tumor treatment.
At present, the primary limitation of cancer therapy is lack of selectivity of therapeutic agents for tumor cells. Current efforts are focused on discovering and developing anticancer agents that selectively target only tumor cells and spare normal tissue to improve the therapeutic index. It has been known that attenuated Salmonella accumulate and replicate preferentially in tumors to a level that is 1,000-fold greater than found in cells from normal tissues. S. typhimurium is a facultative anaerobic bacterium, which is capable of replicating preferentially in tumor cells and inhibition of growth, is associated with lysis of tumors with a necrotic/hypoxic centre. These observations suggest that the tumor targeting bacteria in combination with other antitumor agents, represents a promising strategy for the treatment of primary and metastatic tumors.
Objective:
Evaluation of our new conception i.e: using co-expressed plasmids containing siRNA-mdm2 and p53 and those plasmids will be carried by attenuated Salmonella bacteria and were induced to primary tumor and metastatic tumors for developing more effective treatment for prostate cancer.
Methods:
1. Immunohistochemical staining: Using the immunohistochemical staining to detect the mutant p53 protein and mdm2 expression of normal prostate tissue and prostate cancer.
2. Construction of a recombinant plasmid co-expressing siRNA-mdm2 and p53: Using human mdm2 gene sequences from GenBank, selected suitable target site, synthesized oligonucleotides as DNA template encoding siRNA- mdm2, annealed and ligated into pGCsilencer-U6/Neo/GFP siRNA expression vector to construct plasmid pGCsiRNA-mdm2; amplified U6 promoter and the sequence of SiRNA-Stat3 by using pGCsiRNA-mdm2 plasmid as template by PCR, then cloned into plasmid pcDNA3.1(+) eukaryotic expression vector, designed plasmid pU6 siRNA-mdm2. Amplified the sequence of GRIM-19 gene by using pQE40-p53 plasmid as template by PCR, then cloned into pQE40-p53 vector to construct a plasmid pcDNA3.1-U6-si-mdm2-p53 (Pmp53) that co-expressed both siRNA- mdm2 and p53.
3. Studies in vitro:
The prostate cancer cell line PC-3, were transfected with plasmids siRNA-scramble、siRNA-mdm2、p53 and Pmp53. To determine the expression levels of the mdm2 siRNA and p53 after transfection, the semi-quantitative RT-PCR analysis and Western blot analyses with the samples extracted from transfected and control cells were performed to detect the expression levels of related genes and proteins(mdm2、p53、p21、E2F-1、pRb、HIF-1α). The cells were also analyzed for cell cycle phase distribution by flow cytometry, and the early apoptosis rate were observed by Annexin V-FITC kit and DAPI staining. MTT assay were used to detect the efficacy for inhibition of cell proliferation by different constructs.
4. Studies in vivo:
To study the effects of plasmids siRNA-scramble、siRNA-mdm2、p53 and Pmp53 on prostate tumor growth in vivo, we developed a nude mouse tumor xenograft model. Mice were transplanted via. s.c. with PC-3 cells into the right flank. Attenuated S. typhimurium carried siRNA-scramble、siRNA-mdm2、p53 and Pmp53 were introduced via i.t. into the mice. The TUNEL assay was used to detect the apoptosis of tumor cells. the semi-quantitative RT-PCR analysis and Western blot analysis were used to detect the expression levels of related genes and proteins(mdm2、p53、p21、E2F-1、pRb、HIF-1α). Immunohistochemical staining for p53、mdm2 and PCNA were performed. The ultrastructural changes of tumor cells were observed by TEM.
Results:
1. Overexpressin of mt-p53 and mdm2 proteins in prostate cancer tissues.The results showed higher expression levels of mutant p53 and increased levels of mdm2 proteins in prostate cancer tissues compared with normal prostate tissues. With Spearman analysis, the expression of mdm2 was correlated with p53 protein(rs=0.506,P=0.027).
2. The Pmp53 recombinant plasmids containing both siRNA-mdm2 and p53 were successfully constructed, and confirmed by restriction enzyme digest and DNA sequence analysis.
3. The combinational treatment strategy demonstrated that knockdown of mdm2 gene function by specific siRNA with restoration of the wide type p53 treatment showed a strong efficacy for suppression of PC-3 tumor cells in vitro. MTT assay demonstrated that the Pmp53 treatment group showed the most remarkable suppression effect on PC-3 cell growth, indicating a synergistic effect from the two antitumor factors. RT-PCR and Western blot analyses demonstrated that co-expressed plasmid could not only specifically increase p21 expression level but also can reduce the CDK4,cyclin-D1,HIF-1αexpression. DAPI staining and Annexin V-FITC assays showed both early apoptosis and late apoptosis were happened in all the treated cells excepted two control groups.
4. Attenuated Salmonella carrying Co-expression plasmid Pmp53 inhibited tumor growth of prostate cancer in nude mice. In the group treated with co-expressed p53 and siRNA mdm2, both the average weights and volumes of the tumors were lower than those of other groups. Ceiling method to confirm the attenuated Salmonella carrying the plasmid into the tumor cells and in tumor tissues could copy the high level of 700 times than other organizations; Compared to two control groups, the tumor tissue cells from p53, si-mdm2 and Pmp53 groups were induced apoptosis by using TUNEL staining; decreased PCNA expression was found in the co-expression plasmid group by immunohistochemical staining; in the co-expression plasmid group nuclear heterochromatin on the nuclear membrane or gather into a block with nuclear pyknosis were found by transmission electron microscopy; semi-quantitative RT-PCR and Western blot results showed that co-expression plasmid increased the expression of p21 and inhibited CDK4, cyclin-D1, E2F-1, pRb, HIF-1αexpression by varying degrees.
Conclusion:
1. Higher expression levels of mutant p53 and increased levels of mdm2 proteins detected by immunohistochemical staining in prostate cancer tissues compared with normal prostate tissues.
2. The Pmp53 recombinant plasmids containing both siRNA-mdm2 and p53 were successfully constructed.
3.The combinational treatment strategy demonstrated that knockdown of mdm2 gene function by specific siRNA with restoration of the wide type p53 treatment showed a strong efficacy for suppression of PC-3 tumor cells in vitro. Attenuated Salmonella carrying Co-expression plasmid Pmp53 inhibited tumor growth of prostate cancer in nude mice.
4. The mechanism of the synergistic effect could be mediated through Mechanisms: Because co-expression plasmid inhibition of mdm2 expression, which lifting of the mdm2 negative feedback inhibition of p53 and high expression of wild-type p53, which increased the wild-type p53 tumor growth inhibition effect; this effect affected the expression of downstream genes, such as p21, cyclinD1, Rb and E2F-1 and increases apoptosis, suppressing cell cycling and tumor growth.
5. Because of the high-invasiveness and low pathogenicity of attenuated Salmonella, application of attenuated Salmonella vaccine strains as a carrier of gene therapy showed the effects of cancer treatment, and improved targeting of cancer therapy.
方法:免疫组化技术检测人正常前列腺组织和前列腺癌组织mdm2和p53的表达;基因重组技术构建共表达siRNA-mdm2与p53质粒;真核细胞转染技术将共表达质粒转入前列腺癌PC-3细胞;MTT法检测共表达质粒对PC-3细胞增殖活性的影响;流式细胞术检测共表达质粒对PC-3细胞凋亡的影响;半定量RT-PCR和Western blot检测共表达质粒对mdm2和p53及其相关基因的表达;应用减毒沙门氏菌(Ty21a)携带共表达siRNA-mdm2与p53质粒治疗裸鼠前列腺癌移植瘤,观察其对移植瘤生长的影响。
结果:免疫组化检测到人前列腺癌组织中mdm2和mt-p53高表达,与正常前列腺组织表达有显著差异性,两者呈正相关;基因重组技术成功构建了共表达siRNA-mdm2与p53质粒;MTT检测到共表达质粒对PC-3细胞有抑制增殖作用;流式细胞术检测到共表达质粒对PC-3细胞有促进凋亡作用;透射电镜观察到共表达质粒治疗组肿瘤细胞核固缩等形态学变化;半定量RT-PCR和Western blot检测到共表达质粒促进了P21的表达,而CDK4,cyclin-D1, HIF-1α,pRb,E2F-1的表达被抑制;减毒沙门氏菌携带的共表达siRNA-mdm2与p53质粒明显增强抑制了裸鼠前列腺癌移植瘤的生长;减毒沙门氏菌作为siRNA-mdm2与p53共表达质粒的运载体,起到了靶向性治疗作用。
结论:共表达siRNA-mdm2与p53质粒抑制了前列腺癌细胞PC-3的增殖;减毒沙门氏菌携带共表达siRNA-mdm2与p53质粒对裸鼠前列腺癌移植瘤具有显著的治疗作用。本研究首次构建了共表达siRNA-mdm2与p53质粒,并用减毒沙门氏菌人用疫苗株携带共表达质粒治疗裸鼠前列腺癌移植瘤,为临床肿瘤多基因联合治疗奠定实验基础。
Prostate cancer is the most common cancer in American men. Recently the incidence rate of prostate cancer has increased rapidly in China. Men currently diagnosed at the early stages of prostate cancer can, in many cases, be effectively treated by surgery or radiation. However, in one third of the patients, the disease will recur and ultimately develop into hormone-refractory prostate cancer and metastatic prostate cancers that are essentially incurable. As a new treatment of tumor gene therapy is thought highly of increasingly.
P53 gene is an important tumor suppressor gene, which by preventing cell replication and promoting apoptosis to maintain genomic stability, the maintenance of normal cell growth, and inhibit the proliferation of malignant cells, and be a negative effect on growth regulation. Its mutation and inactivation plays an important role in the process in tumor growth in and infiltration. P53 inactivation showed over-expression of mutant p53. Mutant p53 protein not only showed the loss of the normal tumor suppressor role, but also promoted normal cells to the malignant transformation. It showed that p53 gene mutations may be closely related to a variety of human tumors. In lung cancer, colon cancer, breast cancer, liver cancer, prostate cancer, bladder cancer, ovarian cancer, brain tumor, nasopharyngeal carcinoma, there are reports of high expression of p53. It is reported that nearly half of prostate cancer positive for mutant p53 expression, p53 mutation or deletion is closely related with prostate cancer invasion, metastasis and prognosis.
Mouse double minutes -2 gene (mdm2) is an proto-oncogene. mdm2 gene transcription as a p53 target gene can be induced by wild-type p53 to enhance transcription, and the expression of mdm2 protein product can in turn format the complex product with tumor suppressor gene p53 protein by blocking its transcriptional activity, exporting of p53 protein into the cytoplasm and by promoting the degradation of the p53 protein .At the same time, it can stable the mutant p53 protein, thereby blocking the cell growth inhibition of p53. Both of them format p53 / mdm2 negative feedback loop regulation, so that cells of p53 / mdm2 ratio remained constant in order to ensure normal growth of cells. The most important role of mdm2 in vivo is to inhibiting the transcription and anti-tumor activity of wild-type p53 protein. Researches have shown that the abnormity of mdm2-p53 self-regulating loop, not only plays an important role in tumor occurrence and development, but also is closely related to the tumor treatment.
At present, the primary limitation of cancer therapy is lack of selectivity of therapeutic agents for tumor cells. Current efforts are focused on discovering and developing anticancer agents that selectively target only tumor cells and spare normal tissue to improve the therapeutic index. It has been known that attenuated Salmonella accumulate and replicate preferentially in tumors to a level that is 1,000-fold greater than found in cells from normal tissues. S. typhimurium is a facultative anaerobic bacterium, which is capable of replicating preferentially in tumor cells and inhibition of growth, is associated with lysis of tumors with a necrotic/hypoxic centre. These observations suggest that the tumor targeting bacteria in combination with other antitumor agents, represents a promising strategy for the treatment of primary and metastatic tumors.
Objective:
Evaluation of our new conception i.e: using co-expressed plasmids containing siRNA-mdm2 and p53 and those plasmids will be carried by attenuated Salmonella bacteria and were induced to primary tumor and metastatic tumors for developing more effective treatment for prostate cancer.
Methods:
1. Immunohistochemical staining: Using the immunohistochemical staining to detect the mutant p53 protein and mdm2 expression of normal prostate tissue and prostate cancer.
2. Construction of a recombinant plasmid co-expressing siRNA-mdm2 and p53: Using human mdm2 gene sequences from GenBank, selected suitable target site, synthesized oligonucleotides as DNA template encoding siRNA- mdm2, annealed and ligated into pGCsilencer-U6/Neo/GFP siRNA expression vector to construct plasmid pGCsiRNA-mdm2; amplified U6 promoter and the sequence of SiRNA-Stat3 by using pGCsiRNA-mdm2 plasmid as template by PCR, then cloned into plasmid pcDNA3.1(+) eukaryotic expression vector, designed plasmid pU6 siRNA-mdm2. Amplified the sequence of GRIM-19 gene by using pQE40-p53 plasmid as template by PCR, then cloned into pQE40-p53 vector to construct a plasmid pcDNA3.1-U6-si-mdm2-p53 (Pmp53) that co-expressed both siRNA- mdm2 and p53.
3. Studies in vitro:
The prostate cancer cell line PC-3, were transfected with plasmids siRNA-scramble、siRNA-mdm2、p53 and Pmp53. To determine the expression levels of the mdm2 siRNA and p53 after transfection, the semi-quantitative RT-PCR analysis and Western blot analyses with the samples extracted from transfected and control cells were performed to detect the expression levels of related genes and proteins(mdm2、p53、p21、E2F-1、pRb、HIF-1α). The cells were also analyzed for cell cycle phase distribution by flow cytometry, and the early apoptosis rate were observed by Annexin V-FITC kit and DAPI staining. MTT assay were used to detect the efficacy for inhibition of cell proliferation by different constructs.
4. Studies in vivo:
To study the effects of plasmids siRNA-scramble、siRNA-mdm2、p53 and Pmp53 on prostate tumor growth in vivo, we developed a nude mouse tumor xenograft model. Mice were transplanted via. s.c. with PC-3 cells into the right flank. Attenuated S. typhimurium carried siRNA-scramble、siRNA-mdm2、p53 and Pmp53 were introduced via i.t. into the mice. The TUNEL assay was used to detect the apoptosis of tumor cells. the semi-quantitative RT-PCR analysis and Western blot analysis were used to detect the expression levels of related genes and proteins(mdm2、p53、p21、E2F-1、pRb、HIF-1α). Immunohistochemical staining for p53、mdm2 and PCNA were performed. The ultrastructural changes of tumor cells were observed by TEM.
Results:
1. Overexpressin of mt-p53 and mdm2 proteins in prostate cancer tissues.The results showed higher expression levels of mutant p53 and increased levels of mdm2 proteins in prostate cancer tissues compared with normal prostate tissues. With Spearman analysis, the expression of mdm2 was correlated with p53 protein(rs=0.506,P=0.027).
2. The Pmp53 recombinant plasmids containing both siRNA-mdm2 and p53 were successfully constructed, and confirmed by restriction enzyme digest and DNA sequence analysis.
3. The combinational treatment strategy demonstrated that knockdown of mdm2 gene function by specific siRNA with restoration of the wide type p53 treatment showed a strong efficacy for suppression of PC-3 tumor cells in vitro. MTT assay demonstrated that the Pmp53 treatment group showed the most remarkable suppression effect on PC-3 cell growth, indicating a synergistic effect from the two antitumor factors. RT-PCR and Western blot analyses demonstrated that co-expressed plasmid could not only specifically increase p21 expression level but also can reduce the CDK4,cyclin-D1,HIF-1αexpression. DAPI staining and Annexin V-FITC assays showed both early apoptosis and late apoptosis were happened in all the treated cells excepted two control groups.
4. Attenuated Salmonella carrying Co-expression plasmid Pmp53 inhibited tumor growth of prostate cancer in nude mice. In the group treated with co-expressed p53 and siRNA mdm2, both the average weights and volumes of the tumors were lower than those of other groups. Ceiling method to confirm the attenuated Salmonella carrying the plasmid into the tumor cells and in tumor tissues could copy the high level of 700 times than other organizations; Compared to two control groups, the tumor tissue cells from p53, si-mdm2 and Pmp53 groups were induced apoptosis by using TUNEL staining; decreased PCNA expression was found in the co-expression plasmid group by immunohistochemical staining; in the co-expression plasmid group nuclear heterochromatin on the nuclear membrane or gather into a block with nuclear pyknosis were found by transmission electron microscopy; semi-quantitative RT-PCR and Western blot results showed that co-expression plasmid increased the expression of p21 and inhibited CDK4, cyclin-D1, E2F-1, pRb, HIF-1αexpression by varying degrees.
Conclusion:
1. Higher expression levels of mutant p53 and increased levels of mdm2 proteins detected by immunohistochemical staining in prostate cancer tissues compared with normal prostate tissues.
2. The Pmp53 recombinant plasmids containing both siRNA-mdm2 and p53 were successfully constructed.
3.The combinational treatment strategy demonstrated that knockdown of mdm2 gene function by specific siRNA with restoration of the wide type p53 treatment showed a strong efficacy for suppression of PC-3 tumor cells in vitro. Attenuated Salmonella carrying Co-expression plasmid Pmp53 inhibited tumor growth of prostate cancer in nude mice.
4. The mechanism of the synergistic effect could be mediated through Mechanisms: Because co-expression plasmid inhibition of mdm2 expression, which lifting of the mdm2 negative feedback inhibition of p53 and high expression of wild-type p53, which increased the wild-type p53 tumor growth inhibition effect; this effect affected the expression of downstream genes, such as p21, cyclinD1, Rb and E2F-1 and increases apoptosis, suppressing cell cycling and tumor growth.
5. Because of the high-invasiveness and low pathogenicity of attenuated Salmonella, application of attenuated Salmonella vaccine strains as a carrier of gene therapy showed the effects of cancer treatment, and improved targeting of cancer therapy.
引文
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