针对PTN重组慢病毒介导的siRNA技术在小细胞肺癌基因治疗中的实验研究
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摘要
目的构建针对多效蛋白(pleiotrophin,PTN)基因的小干涉RNA(siRNA)慢病毒表达载体并观察其对人小细胞肺癌H446细胞株PTN表达抑制及对细胞生长及凋亡的影响。同时观察PTN基因沉默后,人小细胞肺癌H446细胞中与血管新生、肿瘤生长、侵袭过程相关的血管内皮细胞生长因子(VEGF)、angiomotin(Amot)、schlafen5(Slfn5)和金属蛋白酶9(MMP-9)4种基因的表达变化。构建人小细胞肺癌H446细胞裸鼠异种移植瘤模型,观察PTN基因RNA干扰病毒对移植瘤瘤体生长的抑制作用。
方法利用逆转录聚合酶链反应(RT-PCR)和Western blot方法检测PTN在H446细胞中的表达。设计四对针对PTN基因的小发夹RNA(shRNA)序列,与Plvthm载体连接,构建慢病毒表达载体LV(lentiviral)-shPTN,连接产物转化到DH5α感受态细胞,阳性克隆测序鉴定。再用LV-shPTN与pRsv-REV、pMDlg-pRRE、pMD2G三种质粒共转染293T细胞,小量包装与纯化产生慢病毒颗粒。病毒感染H446细胞后,用荧光定量PCR及Western blotting检测细胞中PTN基因的表达。选择对PTN基因干扰效率最高的候选慢病毒载体进行大量包装、纯化及病毒滴度测定。将获得的病毒感染H446细胞,实验分为正常未干扰细胞组、感染空对照病毒的阴性对照组、感染PTN基因RNA干扰病毒抑制组、化疗组及感染PTN基因RNA干扰病毒抑制加化疗组。采用四甲基偶氮唑盐比色法(MTT)检测细胞生长,流式细胞仪(FCM)分析细胞凋亡。RT-PCR检测未干扰细胞组、阴性对照组、PTN抑制组和PTN抑制加化疗组细胞中Amot、Slfn5、MMP-9和VEGF的表达。采用H446细胞直接皮下接种的方法构建人小细胞肺癌H446细胞裸鼠异种移植瘤动物模型,分为正常未干扰组,化疗(顺铂)组,干扰PTN的病毒组,化疗+干扰PTN的病毒组和阴性病毒对照组。瘤体附近多点皮下注射病毒或顺铂后,分别于第1、2、7、15天测量瘤体体积。并在治疗第15天分别用RT-PCR和Western blot方法检测正常未干扰组、阴性病毒对照组及干扰PTN的病毒组中PTN的表达。
结果RT-PCR和Western blot检测结果均表明,PTN基因在H446细胞中表达显著高于H460细胞。构建的慢病毒载体经测序验证正确。所构建的shRNA序列(GCAGCTGTGGATACTGCTGAA)对PTN mRNA的抑制效率为72%,对PTN蛋白的抑制效率为59.2%。大量包装与纯化后病毒滴度为1×108 TU/ml。PTN基因抑制组的H446细胞活力显著低于正常未干扰组和阴性对照组细胞,基因抑制联合化疗组较单纯基因抑制组及化疗组细胞活力下降,细胞凋亡率增高,并具呈浓度依赖性。PTN基因沉默后,H446细胞中Slfn5和MMP-9的表达分别较阴性对照组上调了165.1%和47.3%,而Amot和VEGF的表达分别较阴性对照组下调了33.1%和26.6%。协同化疗后,上述趋势更为明显。动物实验瘤体组织中干扰PTN病毒组PTN mRNA和PTN蛋白的表达明显低于正常未干扰组及阴性病毒对照组,抑制率为分别为39%及28%。干扰PTN病毒组瘤体体积显著小于正常未干扰组及阴性病毒对照组,若协同化疗则瘤体缩小更明显。
结论构建PTN RNA干涉载体,转染后可有效降低H446细胞PTN的转录和表达,抑制H446细胞的生长并促进其凋亡,并可进一步影响H446细胞增殖和转移相关基因的表达变化。动物实验也显示针对PTN基因靶向治疗可显著抑制移植肿瘤在体内的生长,若与化疗协同则抑制作用更强。有望为小细胞肺癌基因治疗提供一种选择的治疗手段。
Objective To construct of siRNA lentiviral expressing vector targeting PTN(pleiotrophin)gene in human small cell lung cancer H446 cell and to study the RNAi effect on tumor growth and apoptosis of small cell lung cancer. At the same time, to investigate the changes in gene expression profiles of angiomotin (Amot), schlafen5 (Slfn5), metalloproteinase 9 (MMP-9) and vascular endothelial cell growth factor (VEGF) which are associated with the angiogenesis, tumor growth and invasion after gene silencing of pleiotrophin (PTN) in H446 cell of human small cell lung cancer. To construct of human small cell lung cancer H446 cells nude mice xenograft tumor models, and then observe the growth inhibition role of interference PTN virus towards xenograft tumor.
Methods PTN expression in H446 cell was determined by RT-PCR and Western Blotting. Four pairs of small hairpin RNA specific for PTN were designed, synthesized and cloned into the Plvthm vector. The resulting lentiviral vector containing shPTN were confirmed by DNA sequencing named LV-shPTN. 293T cells were co-transfected with LV-shPTN, pRsv-REV, pMDlg-pRRE and pMD2G, then packed and purified slightly to produce lentivirus. After infecting H446 cells with recombinant lentivirus, PTN expression were determined by real-time RT-PCR and Western Blotting. Finally we packed and purified the selected lentiviral vector with best interference efficiency in large scale and determined the titer of virus. Use the packed virus to infect H446 cell, the experiment was divided to normal cell group, negative control group, PTN interference group, chemotherapy group and combined group with RNAi and chemotherapy. The effect on cell growth and apoptosis of H446 cell infected with high titer virus were analyzed using MTT and FCM. The expression of Amot, Slfn5, MMP-9 and VEGF were detected using RT-PCR method in nomal non-interference group, negative control group, PTN interference group and combined group with PTN interference and chemotherapy. Use direct subcutaneous inoculation method with H446 cells to construct of human small cell lung cancer H446 cells nude mice xenograft tumor models, the experiment was divided to nomal non-interference group, chemotherapy group, PTN interference virus group, combined group with RNAi and chemotherapy and negative control virus group. After multi-point subcutaneous inject virus or cisplatin near the tumor, the tumor volume were measured separately at No.1,2,7,15 days. At No. 15 day PTN expression in nomal non-interference group, negative control virus group and PTN interference virus group was determined separately by RT-PCR and Western Blotting.
Results The results of RT-PCR and Western blot test showed that PTN expression in H446 cell was higher then in H460. DNA sequencing analysis confirmed that shPTN lentiviral vector was successfully established as expected .The interference efficiency of constructed ShRNA sequence(sGCAGCTGTGGATACTGCTGAA) targeting PTN was as high as 72.1% and 59.2% at the mRNA and protein level respectively in H446 cell line. The titer of concentrated virus was 1×108TU/mL. Compared to normal cells and control group, cell viability of PTN interference group was decreased. Compared to RNAi group and chemotherapy group alone, the combined group with RNAi and chemotherapy showed less cell viability and a higher apoptotic rate in a concentration independent manner of the virus. Compared to negative control group, the expressions of Slfn5 and MMP-9 in H446 cell were increased 165.1% and 47.3% while the ones of Amot and VEGF were down-regulated 33.1% and 26.6% respectively after gene silencing of PTN. The changes of the gene expression profile became more evident when chemotherapy was superimposed on PTN interference. For animial experiments, compared to nomal non-interference group and negative virus control group, the expressions of PTNmRNA and PTN protein in PTN interference virus group were decreased significantly in tumor tissue, the interference efficiency was as high as 39% and 28% respectively. Compared to nomal non-interference group and negative virus control group, the tumor volume of PTN interference virus group was reduced significantly. Reduced tumor volume became more evident when chemotherapy was superimposed on PTN interference.
Conclusion By constructing PTN RNAi vector and tranfecting H446 cell, we can effectively reduce the PTN transcription and expression, inhibit the growth and promote the apoptosis of tumor cells, and then can further influence the expression of proliferation and metastasis-related genes in H446 cell. Animial experiments also showed that targeted therapy for PTN could significantly inhibit the growth of xenograft tumor in vivo.This method may become a useful therapeutic strategy for SCLC overexpressing PTN.
方法利用逆转录聚合酶链反应(RT-PCR)和Western blot方法检测PTN在H446细胞中的表达。设计四对针对PTN基因的小发夹RNA(shRNA)序列,与Plvthm载体连接,构建慢病毒表达载体LV(lentiviral)-shPTN,连接产物转化到DH5α感受态细胞,阳性克隆测序鉴定。再用LV-shPTN与pRsv-REV、pMDlg-pRRE、pMD2G三种质粒共转染293T细胞,小量包装与纯化产生慢病毒颗粒。病毒感染H446细胞后,用荧光定量PCR及Western blotting检测细胞中PTN基因的表达。选择对PTN基因干扰效率最高的候选慢病毒载体进行大量包装、纯化及病毒滴度测定。将获得的病毒感染H446细胞,实验分为正常未干扰细胞组、感染空对照病毒的阴性对照组、感染PTN基因RNA干扰病毒抑制组、化疗组及感染PTN基因RNA干扰病毒抑制加化疗组。采用四甲基偶氮唑盐比色法(MTT)检测细胞生长,流式细胞仪(FCM)分析细胞凋亡。RT-PCR检测未干扰细胞组、阴性对照组、PTN抑制组和PTN抑制加化疗组细胞中Amot、Slfn5、MMP-9和VEGF的表达。采用H446细胞直接皮下接种的方法构建人小细胞肺癌H446细胞裸鼠异种移植瘤动物模型,分为正常未干扰组,化疗(顺铂)组,干扰PTN的病毒组,化疗+干扰PTN的病毒组和阴性病毒对照组。瘤体附近多点皮下注射病毒或顺铂后,分别于第1、2、7、15天测量瘤体体积。并在治疗第15天分别用RT-PCR和Western blot方法检测正常未干扰组、阴性病毒对照组及干扰PTN的病毒组中PTN的表达。
结果RT-PCR和Western blot检测结果均表明,PTN基因在H446细胞中表达显著高于H460细胞。构建的慢病毒载体经测序验证正确。所构建的shRNA序列(GCAGCTGTGGATACTGCTGAA)对PTN mRNA的抑制效率为72%,对PTN蛋白的抑制效率为59.2%。大量包装与纯化后病毒滴度为1×108 TU/ml。PTN基因抑制组的H446细胞活力显著低于正常未干扰组和阴性对照组细胞,基因抑制联合化疗组较单纯基因抑制组及化疗组细胞活力下降,细胞凋亡率增高,并具呈浓度依赖性。PTN基因沉默后,H446细胞中Slfn5和MMP-9的表达分别较阴性对照组上调了165.1%和47.3%,而Amot和VEGF的表达分别较阴性对照组下调了33.1%和26.6%。协同化疗后,上述趋势更为明显。动物实验瘤体组织中干扰PTN病毒组PTN mRNA和PTN蛋白的表达明显低于正常未干扰组及阴性病毒对照组,抑制率为分别为39%及28%。干扰PTN病毒组瘤体体积显著小于正常未干扰组及阴性病毒对照组,若协同化疗则瘤体缩小更明显。
结论构建PTN RNA干涉载体,转染后可有效降低H446细胞PTN的转录和表达,抑制H446细胞的生长并促进其凋亡,并可进一步影响H446细胞增殖和转移相关基因的表达变化。动物实验也显示针对PTN基因靶向治疗可显著抑制移植肿瘤在体内的生长,若与化疗协同则抑制作用更强。有望为小细胞肺癌基因治疗提供一种选择的治疗手段。
Objective To construct of siRNA lentiviral expressing vector targeting PTN(pleiotrophin)gene in human small cell lung cancer H446 cell and to study the RNAi effect on tumor growth and apoptosis of small cell lung cancer. At the same time, to investigate the changes in gene expression profiles of angiomotin (Amot), schlafen5 (Slfn5), metalloproteinase 9 (MMP-9) and vascular endothelial cell growth factor (VEGF) which are associated with the angiogenesis, tumor growth and invasion after gene silencing of pleiotrophin (PTN) in H446 cell of human small cell lung cancer. To construct of human small cell lung cancer H446 cells nude mice xenograft tumor models, and then observe the growth inhibition role of interference PTN virus towards xenograft tumor.
Methods PTN expression in H446 cell was determined by RT-PCR and Western Blotting. Four pairs of small hairpin RNA specific for PTN were designed, synthesized and cloned into the Plvthm vector. The resulting lentiviral vector containing shPTN were confirmed by DNA sequencing named LV-shPTN. 293T cells were co-transfected with LV-shPTN, pRsv-REV, pMDlg-pRRE and pMD2G, then packed and purified slightly to produce lentivirus. After infecting H446 cells with recombinant lentivirus, PTN expression were determined by real-time RT-PCR and Western Blotting. Finally we packed and purified the selected lentiviral vector with best interference efficiency in large scale and determined the titer of virus. Use the packed virus to infect H446 cell, the experiment was divided to normal cell group, negative control group, PTN interference group, chemotherapy group and combined group with RNAi and chemotherapy. The effect on cell growth and apoptosis of H446 cell infected with high titer virus were analyzed using MTT and FCM. The expression of Amot, Slfn5, MMP-9 and VEGF were detected using RT-PCR method in nomal non-interference group, negative control group, PTN interference group and combined group with PTN interference and chemotherapy. Use direct subcutaneous inoculation method with H446 cells to construct of human small cell lung cancer H446 cells nude mice xenograft tumor models, the experiment was divided to nomal non-interference group, chemotherapy group, PTN interference virus group, combined group with RNAi and chemotherapy and negative control virus group. After multi-point subcutaneous inject virus or cisplatin near the tumor, the tumor volume were measured separately at No.1,2,7,15 days. At No. 15 day PTN expression in nomal non-interference group, negative control virus group and PTN interference virus group was determined separately by RT-PCR and Western Blotting.
Results The results of RT-PCR and Western blot test showed that PTN expression in H446 cell was higher then in H460. DNA sequencing analysis confirmed that shPTN lentiviral vector was successfully established as expected .The interference efficiency of constructed ShRNA sequence(sGCAGCTGTGGATACTGCTGAA) targeting PTN was as high as 72.1% and 59.2% at the mRNA and protein level respectively in H446 cell line. The titer of concentrated virus was 1×108TU/mL. Compared to normal cells and control group, cell viability of PTN interference group was decreased. Compared to RNAi group and chemotherapy group alone, the combined group with RNAi and chemotherapy showed less cell viability and a higher apoptotic rate in a concentration independent manner of the virus. Compared to negative control group, the expressions of Slfn5 and MMP-9 in H446 cell were increased 165.1% and 47.3% while the ones of Amot and VEGF were down-regulated 33.1% and 26.6% respectively after gene silencing of PTN. The changes of the gene expression profile became more evident when chemotherapy was superimposed on PTN interference. For animial experiments, compared to nomal non-interference group and negative virus control group, the expressions of PTNmRNA and PTN protein in PTN interference virus group were decreased significantly in tumor tissue, the interference efficiency was as high as 39% and 28% respectively. Compared to nomal non-interference group and negative virus control group, the tumor volume of PTN interference virus group was reduced significantly. Reduced tumor volume became more evident when chemotherapy was superimposed on PTN interference.
Conclusion By constructing PTN RNAi vector and tranfecting H446 cell, we can effectively reduce the PTN transcription and expression, inhibit the growth and promote the apoptosis of tumor cells, and then can further influence the expression of proliferation and metastasis-related genes in H446 cell. Animial experiments also showed that targeted therapy for PTN could significantly inhibit the growth of xenograft tumor in vivo.This method may become a useful therapeutic strategy for SCLC overexpressing PTN.
引文
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