RNA干扰Livin基因表达对膀胱癌细胞增殖与凋亡能力的影响
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摘要
Livin是最近发现的凋亡抑制蛋白(Inhibitor of Apoptosis Proteins, IAPs)家族成员,含有一个BIR结构域和一个RING结构域,可显著抑制细胞内源性和外源性凋亡的发生。已有研究表明,Livin在多种恶性肿瘤组织中(如黑色素瘤,肺癌,直肠癌等)呈现高表达,而在其相应的正常组织中不表达。其阳性表达往往与肿瘤的预后以及对化疗药物的抵抗密切相关。然而在膀胱癌中,Livin的表达情况以及Livin基因与膀胱癌预后以及对化疗敏感性的关系目前研究尚少。我们前期研究结果表明,Livin在膀胱癌标本中的阳性表达率高达78%,并与膀胱癌的分期有密切关系。Livin如何调控膀胱癌细胞的增殖、凋亡以及对化疗的敏感性有待于深入研究。
目的：(1)检测Livin基因在膀胱癌细胞系中的表达情况,并使用RNAi的方法高效特异抑制Livin在膀胱癌细胞中的表达,观察Livin基因对膀胱癌增殖、凋亡以及对化疗敏感性的影响。(2)进一步探讨Livin基因与另两种凋亡抑制蛋白XIAP和Survivin在调节膀胱癌增殖与凋亡过程中是否存在协同作用。(3)初步探讨超声辐照超声微泡转染siRNA的有效参数和转染效率,为以Livin基因为靶点治疗膀胱癌寻找有效的治疗策略。
方法：(1)通过RT-PCR的方法检测Livin两条剪接异构体mRNA在膀胱癌细胞系EJ, T24,5673, BIU-87中的表达情况。使用免疫细胞化学和Western blot的方法进一步检测Livin-α, Livin-β蛋白在上述四种细胞系中的表达情况。通过生物信息学的方法筛选能够高效特异抑制Livin表达的siRNA,并通过Western blot实验观察其下调Livin在人膀胱癌T24细胞中表达的效率。(2)通过胎盘蓝计数以及克隆形成实验检测下调Livin基因表达对人膀胱癌T24细胞增殖能力的影响。使用TUNEL实验检测下调Livin基因表达后T24细胞凋亡敏感性的变化,并通过Western blot的方法检测下调Livin表达后其相关Caspase蛋白的表达变化。(3)通过siRNA介导的联合干扰Livin,XIAP和Survivin三种IAPs基因在T24细胞中的表达,使用MTT实验和克隆形成实验比较联合干扰与单独干扰IAPs对膀胱癌细胞增殖能力的影响。使用Annexin-V—PI双重染色比较联合抑制与单独抑制IAPs对膀胱癌细胞凋亡能力的影响。(4)使用超声微泡的方法向T24细胞中转染荧光标记的siRNA小片段,通过荧光显微镜和流式细胞仪观察超声微泡介导基因转染的效率,并通过MTT实验评估超声微泡介导基因转染对细胞活力的影响。
结果：
1. Livin在膀胱癌细胞系中的表达以及Livin特异性siRNA的筛选
在四种膀胱癌细胞系EJ,T24,5673,BIU-87中Livin的两条异构体只有Livin-α在膀胱癌细胞系中阳性表达,Livin-β阴性表达。RT-PCR结果显示,Livin-α和Livin-β在膀胱癌细胞系中的这种表达差异产生在转录水平,而不是由转录后翻译或翻译后蛋白修饰降解引起,Livin-βmRNA在膀胱癌细胞系中阴性表达。免疫细胞化学结果提示Livin主要在膀胱癌细胞浆内表达。Western blot结果进一步证实,在蛋白水平仅有Livin-α阳性表达,Livin-β阴性表达。通过生物信息学的方法筛选出五种Livin特异性siRNA,使用Western blot的方法检测每种siRNA在T24细胞中的干扰效率,结果表明5种siRNA均能够有效的抑制Livin基因的表达。
2.下调Livin基因的表达对膀胱癌T24细胞增殖与凋亡的影响
胎盘蓝计数结果表明,下调Livin基因在膀胱癌T24细胞中的表达可以有效的抑制膀胱癌的生长。克隆形成实验表明,与siRNA-NC相比,siRNA-Livin能够显著降低T24细胞的克隆形成能力。TUNEL实验表明,下调Livin的表达仅能轻度增加T24细胞的自发性凋亡,但能够显著提高T24细胞对肿瘤坏死因子TNF-α和化疗药物丝裂霉素的凋亡敏感性。Western blot结果表明下调Livin基因的表达可以显著增加细胞内激活型Caspase-3和激活型Caspase-9的表达,提示Livin通过Caspase依赖途径调节细胞的凋亡。
3.联合抑制Livin,XIAP和Survivin对膀胱癌增殖、凋亡的影响
Western blot实验表明,Livin,XIAP和Survivin在T24细胞中同时呈现明显的高表达,而在人膀胱上皮SV-HUC-1细胞不表达或低表达。siRNA介导的多基因联合抑制可以有效的抑制Livin,XIAP和Survivin在膀胱癌T24细胞中的表达。流式细胞(Annexin-V—PI双重染色)结果表明,与单个抑制IAP的表达相比,联合抑制IAPs的表达可以显著触发膀胱癌T24细胞的自发性凋亡,增加膀胱癌细胞对化疗药物的敏感性。MTT实验和克隆形成实验结果表明,联合抑制IAPs的表达能够更加明显的抑制膀胱癌细胞的增殖能力和克隆形成能力。另外,联合抑制IAPs的表达能够明显增加激活型Caspase-3,激活型Caspase-7和激活型Caspase-9以及胞浆内Smac的表达水平。
4.超声辐照超声微泡介导siRNA转染T24细胞
实验表明,与各阴性对照组相比,超声辐照超声微泡的方法可以明显增加siRNA向T24细胞中的转染效率。随着超声辐照强度的增加,siRNA的转染效率在一定范围内有所提高,同时也增加了对T24细胞毒性。与脂质体介导的siRNA体外转染相比,超声辐照超声微泡介导的siRNA转染效率仍然较低。以上实验说明,超声微泡是一种较为可行的基因转染方法,然而其具体的转染方法以及转染条件等技术性问题还有待于进一步解决。
结论：
1.下调Livin在T24细胞中的表达可以有效的抑制膀胱癌的生长,降低其克隆形成能力,提高T24细胞对肿瘤坏死因子TNF-α和化疗药物丝裂霉素的凋亡敏感性。
2.联合抑制Livin, XIAP和Survivin的表达能够更加显著的抑制膀胱癌细胞的生长,纠正膀胱癌细胞的凋亡缺陷,触发膀胱癌细胞的自发性凋亡,增加膀胱癌细胞对化疗药物的敏感性。
3.超声辐照超声微泡的方法可以明显增加siRNA向T24细胞中的转染效率。然而在现有的技术条件下,其细胞体外转染效率仍然低于传统的脂质体介导的基因转染。
Livin is the latest found IAP family member, containing one BIR do-main and one RING domain, which can potently inhibit both the intrinsic and the extrinsic cell apoptosis. It has been reported that Livin was highly expressed in many type of cancers including melanoma, lung cancer, colon cancer et al, but not expressed in their normal counterparts, and the positive expression of Livin was often correlated with the poor prognosis and resis-tance to chemotherapy. In our previous study, we have found that Livin was highly expressed in bladder cancer tissues, but how dose Livin regulate bladder cancer proliferation; apoptosis and chemosensitivity need further study.
Objective:(1) Examining the expression of Livin in bladder cancer cell lines and knockdown its expression by RNAi to observe the effect on bladder cancer cell proliferation, apoptosis and chemosensitivity.(2) To determine whether could Livin, XIAP and Survivin synergistically regulate proliferation, apoptosis and chemosensitivity in bladder cancer. (3) Inves-tigating the optimal parameter of ultrasound destruction of microbubble mediated siRNA transfection to explore a possible gene delivery strategy for bladder cancer gene therapy.
Methods:RT-PCR was used to exam the mRNA expression of the two Livin isoforms in bladder cancer cell lines including EJ, T24,5637, and BIU-87. Immunocytochemistry and Western blot assays were performed to determine the Livin protein expression in bladder cancer cell lines. Trypan blue staining and colony formation assay was performed to analyze the ef-fect of Livin knockdown on T24 cell proliferation. TUNEL assay was per-formed to analyze the effect of Livin knockdown on T24 cell sensitivity to proapoptotic stimuli. Combined knockdown of Livin, XIAP, and Survivin was achieved by siRNAs. MTT assay and colony formation assay were performed to analyze the inhibitory effect of combined IAPs knockdown on T24 cell growth. Annexin-V—PI double staining was performed to analyze the effect of combined IAPs knockdown on T24 cell apoptosis. FITC la-beled siRNA was transfected into T24 cells by ultrasound destruction of microbubble. Transfection efficiencies were observed by fluorescence mi-croscope and flow cytometry and the MTT assay was performed to observe the effect on cell viability.
Results:Livin gene was highly expressed in the four kinds of bladder cancer cell lines. However, only the Livin-αisoform expressed in bladder cancer cell lines, but not Livin-β, both at the mRNA and the protein level. Silencing Livin expression could significantly inhibit T24 cell proliferation, promote sensitivity to proapoptotic stimuli. Combined knockdown of all three genes (Livin, XIAP and Survivin) synergistically inhibited prolifera-tion and transformation ability, and promoted cell apoptotic sensitivity to chemotherapy in the high grade bladder cancer T24 cells. Furthermore, combined knockdown of Livin, XIAP and Survivin markedly increased the abundance of active Caspase-3, active Caspase-7 and active Caspase-9, as well as increased the abundance of the cytosolic Smac. Ultrasound destruc-tion of microbubble has an obvious effect of promoting gene transfection. However, the efficiency of microbbuble mediated transfection of siRNA to T24 cell is about 30% which is still lower than the traditional liposome mediated gene transfection.
Conclusion:Knockdown of Livin expression could significantly in-hibit T24 cell growth ability, promote sensitivity to proapoptotic stimuli. The combined knockdown of the three IAP genes (Livin, XIAP, and Sur-vivin) could greatly increase the spontaneous cell apoptosis and have a synergistic effect on regulation of cell growth and apoptosis. Microbubble mediated siRNA transfection might be a potent gene delivery technique in cancer gene therapy.
目的：(1)检测Livin基因在膀胱癌细胞系中的表达情况,并使用RNAi的方法高效特异抑制Livin在膀胱癌细胞中的表达,观察Livin基因对膀胱癌增殖、凋亡以及对化疗敏感性的影响。(2)进一步探讨Livin基因与另两种凋亡抑制蛋白XIAP和Survivin在调节膀胱癌增殖与凋亡过程中是否存在协同作用。(3)初步探讨超声辐照超声微泡转染siRNA的有效参数和转染效率,为以Livin基因为靶点治疗膀胱癌寻找有效的治疗策略。
方法：(1)通过RT-PCR的方法检测Livin两条剪接异构体mRNA在膀胱癌细胞系EJ, T24,5673, BIU-87中的表达情况。使用免疫细胞化学和Western blot的方法进一步检测Livin-α, Livin-β蛋白在上述四种细胞系中的表达情况。通过生物信息学的方法筛选能够高效特异抑制Livin表达的siRNA,并通过Western blot实验观察其下调Livin在人膀胱癌T24细胞中表达的效率。(2)通过胎盘蓝计数以及克隆形成实验检测下调Livin基因表达对人膀胱癌T24细胞增殖能力的影响。使用TUNEL实验检测下调Livin基因表达后T24细胞凋亡敏感性的变化,并通过Western blot的方法检测下调Livin表达后其相关Caspase蛋白的表达变化。(3)通过siRNA介导的联合干扰Livin,XIAP和Survivin三种IAPs基因在T24细胞中的表达,使用MTT实验和克隆形成实验比较联合干扰与单独干扰IAPs对膀胱癌细胞增殖能力的影响。使用Annexin-V—PI双重染色比较联合抑制与单独抑制IAPs对膀胱癌细胞凋亡能力的影响。(4)使用超声微泡的方法向T24细胞中转染荧光标记的siRNA小片段,通过荧光显微镜和流式细胞仪观察超声微泡介导基因转染的效率,并通过MTT实验评估超声微泡介导基因转染对细胞活力的影响。
结果：
1. Livin在膀胱癌细胞系中的表达以及Livin特异性siRNA的筛选
在四种膀胱癌细胞系EJ,T24,5673,BIU-87中Livin的两条异构体只有Livin-α在膀胱癌细胞系中阳性表达,Livin-β阴性表达。RT-PCR结果显示,Livin-α和Livin-β在膀胱癌细胞系中的这种表达差异产生在转录水平,而不是由转录后翻译或翻译后蛋白修饰降解引起,Livin-βmRNA在膀胱癌细胞系中阴性表达。免疫细胞化学结果提示Livin主要在膀胱癌细胞浆内表达。Western blot结果进一步证实,在蛋白水平仅有Livin-α阳性表达,Livin-β阴性表达。通过生物信息学的方法筛选出五种Livin特异性siRNA,使用Western blot的方法检测每种siRNA在T24细胞中的干扰效率,结果表明5种siRNA均能够有效的抑制Livin基因的表达。
2.下调Livin基因的表达对膀胱癌T24细胞增殖与凋亡的影响
胎盘蓝计数结果表明,下调Livin基因在膀胱癌T24细胞中的表达可以有效的抑制膀胱癌的生长。克隆形成实验表明,与siRNA-NC相比,siRNA-Livin能够显著降低T24细胞的克隆形成能力。TUNEL实验表明,下调Livin的表达仅能轻度增加T24细胞的自发性凋亡,但能够显著提高T24细胞对肿瘤坏死因子TNF-α和化疗药物丝裂霉素的凋亡敏感性。Western blot结果表明下调Livin基因的表达可以显著增加细胞内激活型Caspase-3和激活型Caspase-9的表达,提示Livin通过Caspase依赖途径调节细胞的凋亡。
3.联合抑制Livin,XIAP和Survivin对膀胱癌增殖、凋亡的影响
Western blot实验表明,Livin,XIAP和Survivin在T24细胞中同时呈现明显的高表达,而在人膀胱上皮SV-HUC-1细胞不表达或低表达。siRNA介导的多基因联合抑制可以有效的抑制Livin,XIAP和Survivin在膀胱癌T24细胞中的表达。流式细胞(Annexin-V—PI双重染色)结果表明,与单个抑制IAP的表达相比,联合抑制IAPs的表达可以显著触发膀胱癌T24细胞的自发性凋亡,增加膀胱癌细胞对化疗药物的敏感性。MTT实验和克隆形成实验结果表明,联合抑制IAPs的表达能够更加明显的抑制膀胱癌细胞的增殖能力和克隆形成能力。另外,联合抑制IAPs的表达能够明显增加激活型Caspase-3,激活型Caspase-7和激活型Caspase-9以及胞浆内Smac的表达水平。
4.超声辐照超声微泡介导siRNA转染T24细胞
实验表明,与各阴性对照组相比,超声辐照超声微泡的方法可以明显增加siRNA向T24细胞中的转染效率。随着超声辐照强度的增加,siRNA的转染效率在一定范围内有所提高,同时也增加了对T24细胞毒性。与脂质体介导的siRNA体外转染相比,超声辐照超声微泡介导的siRNA转染效率仍然较低。以上实验说明,超声微泡是一种较为可行的基因转染方法,然而其具体的转染方法以及转染条件等技术性问题还有待于进一步解决。
结论：
1.下调Livin在T24细胞中的表达可以有效的抑制膀胱癌的生长,降低其克隆形成能力,提高T24细胞对肿瘤坏死因子TNF-α和化疗药物丝裂霉素的凋亡敏感性。
2.联合抑制Livin, XIAP和Survivin的表达能够更加显著的抑制膀胱癌细胞的生长,纠正膀胱癌细胞的凋亡缺陷,触发膀胱癌细胞的自发性凋亡,增加膀胱癌细胞对化疗药物的敏感性。
3.超声辐照超声微泡的方法可以明显增加siRNA向T24细胞中的转染效率。然而在现有的技术条件下,其细胞体外转染效率仍然低于传统的脂质体介导的基因转染。
Livin is the latest found IAP family member, containing one BIR do-main and one RING domain, which can potently inhibit both the intrinsic and the extrinsic cell apoptosis. It has been reported that Livin was highly expressed in many type of cancers including melanoma, lung cancer, colon cancer et al, but not expressed in their normal counterparts, and the positive expression of Livin was often correlated with the poor prognosis and resis-tance to chemotherapy. In our previous study, we have found that Livin was highly expressed in bladder cancer tissues, but how dose Livin regulate bladder cancer proliferation; apoptosis and chemosensitivity need further study.
Objective:(1) Examining the expression of Livin in bladder cancer cell lines and knockdown its expression by RNAi to observe the effect on bladder cancer cell proliferation, apoptosis and chemosensitivity.(2) To determine whether could Livin, XIAP and Survivin synergistically regulate proliferation, apoptosis and chemosensitivity in bladder cancer. (3) Inves-tigating the optimal parameter of ultrasound destruction of microbubble mediated siRNA transfection to explore a possible gene delivery strategy for bladder cancer gene therapy.
Methods:RT-PCR was used to exam the mRNA expression of the two Livin isoforms in bladder cancer cell lines including EJ, T24,5637, and BIU-87. Immunocytochemistry and Western blot assays were performed to determine the Livin protein expression in bladder cancer cell lines. Trypan blue staining and colony formation assay was performed to analyze the ef-fect of Livin knockdown on T24 cell proliferation. TUNEL assay was per-formed to analyze the effect of Livin knockdown on T24 cell sensitivity to proapoptotic stimuli. Combined knockdown of Livin, XIAP, and Survivin was achieved by siRNAs. MTT assay and colony formation assay were performed to analyze the inhibitory effect of combined IAPs knockdown on T24 cell growth. Annexin-V—PI double staining was performed to analyze the effect of combined IAPs knockdown on T24 cell apoptosis. FITC la-beled siRNA was transfected into T24 cells by ultrasound destruction of microbubble. Transfection efficiencies were observed by fluorescence mi-croscope and flow cytometry and the MTT assay was performed to observe the effect on cell viability.
Results:Livin gene was highly expressed in the four kinds of bladder cancer cell lines. However, only the Livin-αisoform expressed in bladder cancer cell lines, but not Livin-β, both at the mRNA and the protein level. Silencing Livin expression could significantly inhibit T24 cell proliferation, promote sensitivity to proapoptotic stimuli. Combined knockdown of all three genes (Livin, XIAP and Survivin) synergistically inhibited prolifera-tion and transformation ability, and promoted cell apoptotic sensitivity to chemotherapy in the high grade bladder cancer T24 cells. Furthermore, combined knockdown of Livin, XIAP and Survivin markedly increased the abundance of active Caspase-3, active Caspase-7 and active Caspase-9, as well as increased the abundance of the cytosolic Smac. Ultrasound destruc-tion of microbubble has an obvious effect of promoting gene transfection. However, the efficiency of microbbuble mediated transfection of siRNA to T24 cell is about 30% which is still lower than the traditional liposome mediated gene transfection.
Conclusion:Knockdown of Livin expression could significantly in-hibit T24 cell growth ability, promote sensitivity to proapoptotic stimuli. The combined knockdown of the three IAP genes (Livin, XIAP, and Sur-vivin) could greatly increase the spontaneous cell apoptosis and have a synergistic effect on regulation of cell growth and apoptosis. Microbubble mediated siRNA transfection might be a potent gene delivery technique in cancer gene therapy.
引文
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