hTERT启动子调控hNIS和hTPO基因联合转染胶质瘤细胞介导放射性碘治疗的研究
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摘要
研究背景与目的
基因治疗技术是当前肿瘤研究中的热点,但面临着如何提高治疗基因的疗效和解决其靶向性表达的问题,而放射性碘对分化型甲状腺癌细胞则具有着高效、特异性的杀伤效果,其摄碘和贮碘的分子基础在于细胞膜上存在着人钠碘转运体(hNIS)和人甲状腺过氧化物酶(hTPO)。
因此,本研究拟构建并应用重组腺病毒作为基因转移载体,将hNIS和hTPO基因联合转染入胶质瘤细胞,评估转染后细胞的摄碘能力,以及放射性碘在细胞内的代谢动力学变化,并进一步评价放射性碘对胶质瘤细胞的杀伤效果。同时在腺病毒载体中引入人端粒酶逆转录酶(hTERT)启动子,通过实验分析其靶向性引导hNIS在胶质瘤细胞中特异性表达的作用。
方法
1、使用RT-PCR和荧光定量PCR检测多种肿瘤及正常细胞中的hTERT表达活性；通过PCR及pMD-18T质粒载体对hTERT核心启动子进行扩增和克隆；以pGL3-Basic为载体构建含hTERT启动子和hNIS基因的重组质粒,并通过荧光素酶活性实验检测hTERT启动子在不同细胞中的启动效率
2、应用Adeasy系统构建含目的基因的重组腺病毒载体,并对病毒进行滴度测定和转染细胞后表达产物的鉴定。
3、使用重组腺病毒Ad-hTERT-hNIS单独转染,及与Ad-CMV-hTPO联合转染胶质瘤细胞U251和U87,确定最适感染复数；进行摄125Ⅰ实验、125Ⅰ内、外流实验分析放射性碘在胶质瘤细胞内的代谢动力学变化；通过NaC104抑制实验和有机化测定实验验证hNIS和hTPO的作用；并进行克隆形成实验评估放射性131Ⅰ对不同转染组的细胞的杀伤效果。
结果
1、RT-PCR的结果显示在H460、U251、U87、ARO及FRO等细胞中均存在hTERT mRNA的表达,只是活性的高低不一；而在正常细胞MRC-5中无表达。荧光定量PCR的结果显示在胶质瘤细胞U251和U87内存在hTERT的高活性表达,与内参基因β-actin对照,其相对含量分别为0.18%和0.12%。
2、成功构建并鉴定了含3种不同长度hTERT启动子序列(260 bp、456 bp及1453bp)的pMD-18T和pGL3重组质粒,并成功构建并鉴定了含260 bp hTERT启动子及hNIS基因的重组质粒pGL3-hNIS。
3、荧光素酶活性实验结果显示,在上述肿瘤细胞中,3种hTERT启动子片段均可诱导荧光蛋白的表达,但其启动效率存在差异,其中pGL3-204中的启动子片段(260 bp)在FRO、H460和U251中启动效率最强,可以达到SV40启动子的80%。
4、构建并纯化了重组腺病毒Ad-CMV-hTPO,空斑形成实验测定其滴度约为1.0×109pfu/ml,感染293细胞后行Western blot结果显示在110 kD处可见阳性反应条带,为表达的hTPO目的蛋白。
5、摄碘实验结果显示,单独转染组(Ad-hTERT-hNIS)的胶质瘤细胞U251和U87均具有了较强的摄碘能力,分别提高了30.76倍和29.66倍；而联合转染组(Ad-hTERT-hNIS/Ad-CMV-hTPO)的摄碘能力又均有轻度增高,分别为35.55倍和32.88倍。
6、125Ⅰ的内、外流实验显示单独转染组的胶质瘤细胞能够快速的摄碘,峰值均出现在约40 mmin时；但碘的流出也较迅速,Te约为11-12 min；而联合转染组则可以在一定程度上延缓125Ⅰ的外流,Te约为18-20 mmin。
7、过氯酸盐抑制实验结果显示,不同浓度的NaC104均可抑制转染后胶质瘤细胞对125Ⅰ的摄取,抑制率约为93.50-94.48%。有机化测定实验结果显示,联合转染组细胞内与蛋白结合的125Ⅰ量高于单独转染组,约为后者的3倍。
8、克隆形成实验结果显示经131Ⅰ治疗后,联合转染组的克隆形成率降低得最为明显,U251和U87分别降低了11.37和14.52倍；其次为单独转染组,分别降低了5.52和6.05倍(P均<0.01)。
结论
1、在胶质瘤U251和U87等多种肿瘤细胞中均存在hTERT不同活性的表达,因此可以应用hTERT启动子引导治疗基因在胶质瘤细胞中的特异性表达。而且hTERT核心启动子具有较高的启动效率,可以替代全长启动子引导hNIS基因表达。
2、携带hTERT启动子和hNIS基因,hTPO基因的重组质粒及腺病毒载体构建成功,应用Ad-hTERT-hNIS单独转染胶质瘤细胞后可以使其获得较强的摄碘能力,从而能够介导放射性碘杀伤肿瘤细胞。
3、在单独转染hNIS基因的胶质瘤细胞中碘会快速的外流,与Ad-CMV-hTPO联合转染后可以增加与蛋白结合的碘量,使碘在细胞内的停留时间有所延长,从而提高放射性碘对胶质瘤细胞的杀伤效果。
Background and objectives
Gene therapy is currently one of the major focuses in cancer research. Yet gene therapy is faced with the problems of how to improve its efficacy and to enhance targeted gene product expressions. Radioiodine therapy on differentiated thyroid cancers (DTC) exhibits high efficiency and specificity. The molecular basis of radioiodine uptake and storage by DTC cells is the cellular membrane expression of human sodium iodide symporter (hNIS) and human thyroid peroxidase (hTPO) in DTC cells.
Therefore, this study aimed to construct and utilize recombinant adenovirus (as a gene transfer vector), then to transfect hNIS and hTPO genes into glioma cells. And we also intended to assess the iodine uptake abilities of the transfected cells, to investigate the radioiodine metabolism dynamics in the cells, and to further evaluate the anti-tumor activities of radioiodine on the transfected cells. We then planned to introduce human telomerase reverse transcriptase (hTERT) in adenovirus vector, afterwards hNIS expression changes were analyzed in the transfected glioma cells.
Methods
1. Using RT-PCR and real-time fluorescent quantitative PCR (FQ-PCR, or qPCR) to detect the expression of hTERT of a variety of tumor cell lines and normal cells. By using PCR and pMD-18T vector to amplify and clone the hTERT core promoter. To construct recombinant plasmid containing the hTERT promoter and hNIS gene with pGL3-Basic vector, and to detect promoting efficiency of hTERT promoter with luciferase activity test.
2. By using Adeasy System to build recombinant adenovirus vector containing the target genes, and the virus titer and the expression of targeted genes in transfected cells were analyzed.
3. Using recombinant adenovirus Ad-hTERT-hNIS single transfected and Ad-hTERT-hNIS plus Ad-CMV-hTPO co-transfected U251 and U87 glioma cells to determine the optimal multiplicity of infection (MOI). Metabolism dynamic changes in the glioma cells were tested by 125I uptake,125I influx and efflux experiments. The effectiveness of hNIS and hTPO were tested by NaC104 inhibition experiment and organic measurement experiment. And then clonogenic assay was adopted to determine the anti-tumor activities of 131I on differently transfected cell groups.
Results
1. RT-PCR results showed that the expressions of hTERT mRNA existed in H460, U251, U87, ARO and FRO cells, yet their levels of activities were different. But in normal cells of MRC-5 no expression of hTERT mRNA was found. FQ-PCR results showed that in U251 and U87 glioma cells the expressions of hTERT were very high, their relative concentrations were 0.18% and 0.12% compared with the internal reference ofβ-actin.
2. Successfully constructed and identified plasmids pMD-18T and the pGL3 with 3 different length hTERT promoter sequences (260 bp,456 bp and 1453 bp). And successfully constructed and identified plasmid pGL3-hNIS with 260 bp hTERT promoter and hNIS as well.
3. Luciferase activity assay showed that, in the above tumor cells, all three kinds of hTERT promoter fragments could induce the expression of fluorescent proteins, but differences existed in their efficiencies. Promoter fragment (260 bp) of pGL3-204 in FRO, H460 and U251 cells possessed the strongest efficiencies, which could reach 80% of the SV40 promoter.
4. Construction and purification of the recombinant adenovirus Ad-CMV-hTPO. Measured by plaque formation assay, its titer was shown as approximately 1.0×109 pfu/ml. After infection of 293 cells, Western blot was performed to demonstrate a positive band at 110 kD, which was the target gene expression of protein hTPO.
5. Iodine uptake experiment demonstrated that U251 and U87 glioma cells in single transfection group (Ad-hTERT-hNIS) had enhanced iodine uptake abilities of 30.76 fold and 29.66 fold. And in co-transfection group (Ad-hTERT-hNIS/Ad-CMV-hTPO), the iodine uptake abilities were increased further to 35.55 fold and 32.88 fold, respectively.
6.125I influx and efflux experiments showed that in single transfected glioma cells iodine uptake was rapid, the peak was about 40 minutes. But a rapid efflux of iodine was also observed with Te about 11-12 minutes. However, the co-transfection group could delay the efflux of 125I to a Te of about 18-20 minutes.
7. Perchlorate inhibition test showed that different concentrations of NaC104 could inhibit transfected glioma cells to uptake 125I, the inhibition rate was about 93.50-94.48%. Organic measurement experiment showed that the co-transfected cells possessed higher 125I binding ability (about 3 times) by intracellular proteins than single transfection group.
8. Clonogenic assay demonstrated that after 131I treatment the co-transfection group had the lowest rate of colony formation, with U251 and U87 reduced by 11.37 and 14.52 folds. And the co-transfection group was followed by single transfection group, the reductions were 5.52 and 6.05 folds (P<0.01).
Conclusion
1. In U251 and U87 glioma cells and other tumor cells different expressions and activities of hTERT existed, so the hTERT promoter could be used to guide therapeutic genes to specific expressions in glioma cells. HTERT core promoter had high promoting efficiency, and could be used as a replace of the full length promoter to guide hNIS gene expression.
2. Recombinant plasmid and adenovirus vector containing HTERT promoter, hNIS gene and hTPO gene were constructed successfully. Single transfected glioma cells with Ad-hTERT-hNIS alone could enable the tumor cells to acquire a strong iodine uptake ability, which could mediate the radioiodine treatment on tumor cells.
3. In single transfection glioma cells of hNIS gene, iodine efflux happened very quickly. And the co-transfection with Ad-CMV-hTPO could increase protein binding of iodine, prolong entrapment of iodine in the cells, and to improve radioiodine therapy on glioma cells.
基因治疗技术是当前肿瘤研究中的热点,但面临着如何提高治疗基因的疗效和解决其靶向性表达的问题,而放射性碘对分化型甲状腺癌细胞则具有着高效、特异性的杀伤效果,其摄碘和贮碘的分子基础在于细胞膜上存在着人钠碘转运体(hNIS)和人甲状腺过氧化物酶(hTPO)。
因此,本研究拟构建并应用重组腺病毒作为基因转移载体,将hNIS和hTPO基因联合转染入胶质瘤细胞,评估转染后细胞的摄碘能力,以及放射性碘在细胞内的代谢动力学变化,并进一步评价放射性碘对胶质瘤细胞的杀伤效果。同时在腺病毒载体中引入人端粒酶逆转录酶(hTERT)启动子,通过实验分析其靶向性引导hNIS在胶质瘤细胞中特异性表达的作用。
方法
1、使用RT-PCR和荧光定量PCR检测多种肿瘤及正常细胞中的hTERT表达活性；通过PCR及pMD-18T质粒载体对hTERT核心启动子进行扩增和克隆；以pGL3-Basic为载体构建含hTERT启动子和hNIS基因的重组质粒,并通过荧光素酶活性实验检测hTERT启动子在不同细胞中的启动效率
2、应用Adeasy系统构建含目的基因的重组腺病毒载体,并对病毒进行滴度测定和转染细胞后表达产物的鉴定。
3、使用重组腺病毒Ad-hTERT-hNIS单独转染,及与Ad-CMV-hTPO联合转染胶质瘤细胞U251和U87,确定最适感染复数；进行摄125Ⅰ实验、125Ⅰ内、外流实验分析放射性碘在胶质瘤细胞内的代谢动力学变化；通过NaC104抑制实验和有机化测定实验验证hNIS和hTPO的作用；并进行克隆形成实验评估放射性131Ⅰ对不同转染组的细胞的杀伤效果。
结果
1、RT-PCR的结果显示在H460、U251、U87、ARO及FRO等细胞中均存在hTERT mRNA的表达,只是活性的高低不一；而在正常细胞MRC-5中无表达。荧光定量PCR的结果显示在胶质瘤细胞U251和U87内存在hTERT的高活性表达,与内参基因β-actin对照,其相对含量分别为0.18%和0.12%。
2、成功构建并鉴定了含3种不同长度hTERT启动子序列(260 bp、456 bp及1453bp)的pMD-18T和pGL3重组质粒,并成功构建并鉴定了含260 bp hTERT启动子及hNIS基因的重组质粒pGL3-hNIS。
3、荧光素酶活性实验结果显示,在上述肿瘤细胞中,3种hTERT启动子片段均可诱导荧光蛋白的表达,但其启动效率存在差异,其中pGL3-204中的启动子片段(260 bp)在FRO、H460和U251中启动效率最强,可以达到SV40启动子的80%。
4、构建并纯化了重组腺病毒Ad-CMV-hTPO,空斑形成实验测定其滴度约为1.0×109pfu/ml,感染293细胞后行Western blot结果显示在110 kD处可见阳性反应条带,为表达的hTPO目的蛋白。
5、摄碘实验结果显示,单独转染组(Ad-hTERT-hNIS)的胶质瘤细胞U251和U87均具有了较强的摄碘能力,分别提高了30.76倍和29.66倍；而联合转染组(Ad-hTERT-hNIS/Ad-CMV-hTPO)的摄碘能力又均有轻度增高,分别为35.55倍和32.88倍。
6、125Ⅰ的内、外流实验显示单独转染组的胶质瘤细胞能够快速的摄碘,峰值均出现在约40 mmin时；但碘的流出也较迅速,Te约为11-12 min；而联合转染组则可以在一定程度上延缓125Ⅰ的外流,Te约为18-20 mmin。
7、过氯酸盐抑制实验结果显示,不同浓度的NaC104均可抑制转染后胶质瘤细胞对125Ⅰ的摄取,抑制率约为93.50-94.48%。有机化测定实验结果显示,联合转染组细胞内与蛋白结合的125Ⅰ量高于单独转染组,约为后者的3倍。
8、克隆形成实验结果显示经131Ⅰ治疗后,联合转染组的克隆形成率降低得最为明显,U251和U87分别降低了11.37和14.52倍；其次为单独转染组,分别降低了5.52和6.05倍(P均<0.01)。
结论
1、在胶质瘤U251和U87等多种肿瘤细胞中均存在hTERT不同活性的表达,因此可以应用hTERT启动子引导治疗基因在胶质瘤细胞中的特异性表达。而且hTERT核心启动子具有较高的启动效率,可以替代全长启动子引导hNIS基因表达。
2、携带hTERT启动子和hNIS基因,hTPO基因的重组质粒及腺病毒载体构建成功,应用Ad-hTERT-hNIS单独转染胶质瘤细胞后可以使其获得较强的摄碘能力,从而能够介导放射性碘杀伤肿瘤细胞。
3、在单独转染hNIS基因的胶质瘤细胞中碘会快速的外流,与Ad-CMV-hTPO联合转染后可以增加与蛋白结合的碘量,使碘在细胞内的停留时间有所延长,从而提高放射性碘对胶质瘤细胞的杀伤效果。
Background and objectives
Gene therapy is currently one of the major focuses in cancer research. Yet gene therapy is faced with the problems of how to improve its efficacy and to enhance targeted gene product expressions. Radioiodine therapy on differentiated thyroid cancers (DTC) exhibits high efficiency and specificity. The molecular basis of radioiodine uptake and storage by DTC cells is the cellular membrane expression of human sodium iodide symporter (hNIS) and human thyroid peroxidase (hTPO) in DTC cells.
Therefore, this study aimed to construct and utilize recombinant adenovirus (as a gene transfer vector), then to transfect hNIS and hTPO genes into glioma cells. And we also intended to assess the iodine uptake abilities of the transfected cells, to investigate the radioiodine metabolism dynamics in the cells, and to further evaluate the anti-tumor activities of radioiodine on the transfected cells. We then planned to introduce human telomerase reverse transcriptase (hTERT) in adenovirus vector, afterwards hNIS expression changes were analyzed in the transfected glioma cells.
Methods
1. Using RT-PCR and real-time fluorescent quantitative PCR (FQ-PCR, or qPCR) to detect the expression of hTERT of a variety of tumor cell lines and normal cells. By using PCR and pMD-18T vector to amplify and clone the hTERT core promoter. To construct recombinant plasmid containing the hTERT promoter and hNIS gene with pGL3-Basic vector, and to detect promoting efficiency of hTERT promoter with luciferase activity test.
2. By using Adeasy System to build recombinant adenovirus vector containing the target genes, and the virus titer and the expression of targeted genes in transfected cells were analyzed.
3. Using recombinant adenovirus Ad-hTERT-hNIS single transfected and Ad-hTERT-hNIS plus Ad-CMV-hTPO co-transfected U251 and U87 glioma cells to determine the optimal multiplicity of infection (MOI). Metabolism dynamic changes in the glioma cells were tested by 125I uptake,125I influx and efflux experiments. The effectiveness of hNIS and hTPO were tested by NaC104 inhibition experiment and organic measurement experiment. And then clonogenic assay was adopted to determine the anti-tumor activities of 131I on differently transfected cell groups.
Results
1. RT-PCR results showed that the expressions of hTERT mRNA existed in H460, U251, U87, ARO and FRO cells, yet their levels of activities were different. But in normal cells of MRC-5 no expression of hTERT mRNA was found. FQ-PCR results showed that in U251 and U87 glioma cells the expressions of hTERT were very high, their relative concentrations were 0.18% and 0.12% compared with the internal reference ofβ-actin.
2. Successfully constructed and identified plasmids pMD-18T and the pGL3 with 3 different length hTERT promoter sequences (260 bp,456 bp and 1453 bp). And successfully constructed and identified plasmid pGL3-hNIS with 260 bp hTERT promoter and hNIS as well.
3. Luciferase activity assay showed that, in the above tumor cells, all three kinds of hTERT promoter fragments could induce the expression of fluorescent proteins, but differences existed in their efficiencies. Promoter fragment (260 bp) of pGL3-204 in FRO, H460 and U251 cells possessed the strongest efficiencies, which could reach 80% of the SV40 promoter.
4. Construction and purification of the recombinant adenovirus Ad-CMV-hTPO. Measured by plaque formation assay, its titer was shown as approximately 1.0×109 pfu/ml. After infection of 293 cells, Western blot was performed to demonstrate a positive band at 110 kD, which was the target gene expression of protein hTPO.
5. Iodine uptake experiment demonstrated that U251 and U87 glioma cells in single transfection group (Ad-hTERT-hNIS) had enhanced iodine uptake abilities of 30.76 fold and 29.66 fold. And in co-transfection group (Ad-hTERT-hNIS/Ad-CMV-hTPO), the iodine uptake abilities were increased further to 35.55 fold and 32.88 fold, respectively.
6.125I influx and efflux experiments showed that in single transfected glioma cells iodine uptake was rapid, the peak was about 40 minutes. But a rapid efflux of iodine was also observed with Te about 11-12 minutes. However, the co-transfection group could delay the efflux of 125I to a Te of about 18-20 minutes.
7. Perchlorate inhibition test showed that different concentrations of NaC104 could inhibit transfected glioma cells to uptake 125I, the inhibition rate was about 93.50-94.48%. Organic measurement experiment showed that the co-transfected cells possessed higher 125I binding ability (about 3 times) by intracellular proteins than single transfection group.
8. Clonogenic assay demonstrated that after 131I treatment the co-transfection group had the lowest rate of colony formation, with U251 and U87 reduced by 11.37 and 14.52 folds. And the co-transfection group was followed by single transfection group, the reductions were 5.52 and 6.05 folds (P<0.01).
Conclusion
1. In U251 and U87 glioma cells and other tumor cells different expressions and activities of hTERT existed, so the hTERT promoter could be used to guide therapeutic genes to specific expressions in glioma cells. HTERT core promoter had high promoting efficiency, and could be used as a replace of the full length promoter to guide hNIS gene expression.
2. Recombinant plasmid and adenovirus vector containing HTERT promoter, hNIS gene and hTPO gene were constructed successfully. Single transfected glioma cells with Ad-hTERT-hNIS alone could enable the tumor cells to acquire a strong iodine uptake ability, which could mediate the radioiodine treatment on tumor cells.
3. In single transfection glioma cells of hNIS gene, iodine efflux happened very quickly. And the co-transfection with Ad-CMV-hTPO could increase protein binding of iodine, prolong entrapment of iodine in the cells, and to improve radioiodine therapy on glioma cells.
引文
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