高效靶向调控突变型Bik基因促淋巴瘤细胞凋亡研究
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摘要
目的：Bcl-2家族是细胞凋亡中最重要的家族,包括凋亡抑制蛋白Bcl-2、Bcl-XL、Bcl-w、Mcl-1等及具有凋亡诱导活性的蛋白Bax、Bad、Bik等,Bcl-2家族蛋白表达异常与肿瘤发生发展相关,并且可能与肿瘤细胞对部分化疗药物的敏感性有关。淋巴瘤细胞中普遍存在Bcl-2、Bcl-xL等凋亡抑制蛋白的表达水平上调及Bik等促凋亡蛋白的表达下调,一方面使肿瘤细胞对凋亡的敏感性下降,另一方面也可能导致淋巴瘤细胞对化疗药物产生抵抗。Bik(Bcl-2 interacting killer)作为Bcl-2家族中的一种仅含BH3结构域的凋亡诱导蛋白,相对其他凋亡诱导蛋白而言,能结合的Bcl-2家族凋亡抑制蛋白最多,且与凋亡抑制蛋白中研究最多的Bcl-2及Mcl-1的结合力最强,是常用的治疗基因之一。而将野生型Bik的第33位苏氨酸残基和35位丝氨酸残基替换为门冬氨酸可以模拟这两个残基的磷酸化使其成为突变型Bik(BikDD),这种模拟磷酸化可以提高Bik与凋亡抑制蛋白的结合能力及诱导肿瘤细胞凋亡和抑制肿瘤细胞增殖的能力。
通过转染BikDD(突变型Bik编码基因)提高淋巴瘤细胞中的Bik表达水平可能是淋巴瘤基因治疗的一种有效方法,但外源基因不能在靶部位获得高效表达是目前肿瘤基因治疗面临的突出问题,本研究着重探讨如何实现BikDD在淋巴瘤细胞中的高效特异性表达及研究BikDD表达对淋巴瘤细胞的促凋亡作用。
方法：在研究的第一部分,构建出含生存蛋白(Survivin)启动子、人端粒酶逆转录酶基因(hTERT)启动子及巨细胞病毒(CMV)启动子的荧光素酶表达载体,转染体外培养淋巴瘤细胞株Raji、Ramos、Hut78、U937和肝细胞株chang liver,通过检测荧光素酶表达水平比较不同启动子在淋巴瘤细胞株中的表达效率与特异性,选择在淋巴瘤细胞中具有较高效率及特异性的肿瘤特异性启动子。
第二部分,利用Survivin启动子与WPRE、TSTA和VISA信号放大系统构建出淋巴瘤特异性表达载体S-WPRE、S-TSTA和S-VISA,通过检测细胞转染后的荧光素酶表达水平比较不同信号放大系统在淋巴瘤细胞株中的表达效率,选择在淋巴瘤细胞中具有较高效率的放大系统与Survivin组成淋巴瘤特异性高效表达载体。
在第三部分研究中,我们采用淋巴瘤特异性高效表达载体与BikDD治疗基因转染淋巴瘤细胞和肝细胞,并测定转染后Bik表达水平,观察其对淋巴瘤Bik表达的影响及其对淋巴瘤细胞的生长抑制与促凋亡作用。
结果：(1)Survivin启动子和hTERT启动子在淋巴瘤细胞都具有明显高于阴性对照的活性(p<0.01)。除在hut78细胞中Survivin启动子的活性低于hTERT启动子之外(p<0.05), Survivin启动子和hTERT启动子在淋巴瘤细胞Raji、Ramos、U937细胞中转录活性无明显差异(p>0.05),但Survivin启动子的淋巴瘤特异性明显优于hTERT启动子(p<0.05),故选择其作为进一步构建高效特异性淋巴瘤表达载体的启动子。(2) S-VISA和S-TSTA在Raji、Ramos、Hut78及U937细胞中的荧光素酶表达水平明显优于pGL3-CMV(p<0.05),在肝细胞中的荧光素酶表达水平明显低于pGL3-CMV (p<0.05), S-VSIA在Raji、Ramos、U937中的荧光素酶表达水平高于S-TSTA(p<0.05),分别为655.39% VS 315.35%、413.01% VS 272.33%、653.92%VS 245.00%。而在hut78细胞和chang liver细胞中表达水平无明显差异(p>0.05)。故选择S-VISA作为进一步淋巴瘤促凋亡研究的高效表达载体。(3)我们对于淋巴瘤细胞Bik水平检测提示四种淋巴瘤细胞的Bik表达水平不同程度地低于肝细胞的Bik水平。S-VISA-BikDD转染后能不同程度提高淋巴瘤细胞的Bik表达水平,并且对于淋巴瘤细胞Raji、Ramos、U937和Hut78具有明显的生长抑制作用,对淋巴瘤Raji细胞具有促凋亡作用。
结论：就淋巴瘤细胞和肝细胞而言,Survivin启动子能调控外源基因在淋巴瘤细胞中特异性表达,VISA系统能明显增强Survivin启动子的活性,使目的基因在淋巴瘤细胞中高效特异性表达S-VISA-BikDD能对淋巴瘤细胞造成明显的生长抑制作用及一定的凋亡诱导作用,S-VISA-BikDD是很有潜力的淋巴瘤基因治疗载体。
Bcl-2 family is one of the most important genes families to regulate apoptosis. Bcl-2 family contain anti-apoptotic family members (e.g. Bcl-XL、Bcl-2), and pro-apoptotic family members, such as Bik and Bax. The abnormality of Bcl-2 family not only relates to the genesis and progression of tumors, it also links to the chemosensitivity of some anticancer drugs. The low expression of pro-apoptotic family members or the over expression of anti-apoptotic family members in many lymphoma cells result in the insensitivity of inducing apoptosis as well as the resistance of chemotherapy for lymphoma cells. Bik is one of the most potent BH3-only proteins, shown to interact with more anti-apoptotic family members and have stronger binging force with widely studied Bcl-2 than others pro-apoptotic family members. Bik mutant (BikDD), in which changes were made in T33D and S35D to mimic phosphorylation at these two residues, can enhance its binding affinity with the antiapoptotic proteins Bcl-X1 and Bcl-2 and show more potent than wild-type bik in inducing apoptosis and inhibiting cell proliferation of cancer cells.
Transduction of BikDD gene into lymphoma cells may be a promising method of gene therapy for lymphoma. One of the major obstacles of gene therapy is that the ectopic gene cannot express highly in targeted cells. The objective of this study focuses on how to guarantee BikDD gene expresses highly in lymphoma cell lines and research the apoptotic effects of BikDD on lymphoma cell lines.
In the first part of this study, we generated luciferase vectors contain Survivin promoter, hTERT promoter and CMV promoter respectively. We detected the luciferase expression of vectors in different lymphoma cell lines and hepatic cell line chang liver to evaluate the efficacy and lymphoma specificity of promoters.
In the second part, we constructed three plasmids contained different elements of WPRE, TSTA and VISA under control of Survivin promoter. We detected the luciferase expression of vectors in different lymphoma cell lines and hepatic cell line to select the most efficient amplification system, which would be used to construct high efficient and lymphoma-specific gene expression vectors with Survivin promoter.
In the third part, the lymphoma cell lines Raji, Ramos, U937, hut78 and hepatic cell line chang liver were transfected with the recombinant BikDD vector, which contained a 987 bp human Survivin promoter, a mutant Bik cDNA, as a pro-apoptotic gene, and VISA signal amplification system. Then, Western blot was used to assess the different lymphoma cell lines expression of Bik. We also used the MTT assay and flow cytometry to detect growth inhibition and pro-apoptotic effects on lymphoma cell lines.
Results:The luciferase detection results showed that Survivin promoter was more efficient and lymphoma-specific than hTERT promoter. S-VISA and S-TSTA showed more efficient than pGL3-CMV in lymphoma cell lines Raji, Ramos, Hut78 and U937 (p<0.05), but less efficient than pGL3-CMV in hepatic cell line chang liver. S-VISA was selected as highly efficient and targeted gene expression vector in lymphoma cell lines for its higher efficacy in Raji, Ramos and U937 than S-TSTA (p<0.05)
Results of Western blot showed that Bik expression of lymphoma cells was lower than Bik expression in chang liver cells in different degree, and Bik expression increased in different degree after lymphoma cells were transfected with S-VISA-BikDD plasmid. S-VISA-BikDD resulted in significant growth inhibition in all transfected cell lines except chang liver. S-VISA-BikDD resulted in significant apoptosis in transfected Raji cell line.
Conclusion:So far as lymphoma cells and hepatic cells, the Survivin promoter can make Bik gene expressing targeted in lymphoma cells. VISA system amplifies the activity of Survivin promoter effectively. S-VISA-BikDD pro-apoptotic vector can lead the lymphoma cells to apoptosis and growth inhibition. S-VISA-BikDD is an effective pro-apoptotic vector for gene therapy in lymphoma.
通过转染BikDD(突变型Bik编码基因)提高淋巴瘤细胞中的Bik表达水平可能是淋巴瘤基因治疗的一种有效方法,但外源基因不能在靶部位获得高效表达是目前肿瘤基因治疗面临的突出问题,本研究着重探讨如何实现BikDD在淋巴瘤细胞中的高效特异性表达及研究BikDD表达对淋巴瘤细胞的促凋亡作用。
方法：在研究的第一部分,构建出含生存蛋白(Survivin)启动子、人端粒酶逆转录酶基因(hTERT)启动子及巨细胞病毒(CMV)启动子的荧光素酶表达载体,转染体外培养淋巴瘤细胞株Raji、Ramos、Hut78、U937和肝细胞株chang liver,通过检测荧光素酶表达水平比较不同启动子在淋巴瘤细胞株中的表达效率与特异性,选择在淋巴瘤细胞中具有较高效率及特异性的肿瘤特异性启动子。
第二部分,利用Survivin启动子与WPRE、TSTA和VISA信号放大系统构建出淋巴瘤特异性表达载体S-WPRE、S-TSTA和S-VISA,通过检测细胞转染后的荧光素酶表达水平比较不同信号放大系统在淋巴瘤细胞株中的表达效率,选择在淋巴瘤细胞中具有较高效率的放大系统与Survivin组成淋巴瘤特异性高效表达载体。
在第三部分研究中,我们采用淋巴瘤特异性高效表达载体与BikDD治疗基因转染淋巴瘤细胞和肝细胞,并测定转染后Bik表达水平,观察其对淋巴瘤Bik表达的影响及其对淋巴瘤细胞的生长抑制与促凋亡作用。
结果：(1)Survivin启动子和hTERT启动子在淋巴瘤细胞都具有明显高于阴性对照的活性(p<0.01)。除在hut78细胞中Survivin启动子的活性低于hTERT启动子之外(p<0.05), Survivin启动子和hTERT启动子在淋巴瘤细胞Raji、Ramos、U937细胞中转录活性无明显差异(p>0.05),但Survivin启动子的淋巴瘤特异性明显优于hTERT启动子(p<0.05),故选择其作为进一步构建高效特异性淋巴瘤表达载体的启动子。(2) S-VISA和S-TSTA在Raji、Ramos、Hut78及U937细胞中的荧光素酶表达水平明显优于pGL3-CMV(p<0.05),在肝细胞中的荧光素酶表达水平明显低于pGL3-CMV (p<0.05), S-VSIA在Raji、Ramos、U937中的荧光素酶表达水平高于S-TSTA(p<0.05),分别为655.39% VS 315.35%、413.01% VS 272.33%、653.92%VS 245.00%。而在hut78细胞和chang liver细胞中表达水平无明显差异(p>0.05)。故选择S-VISA作为进一步淋巴瘤促凋亡研究的高效表达载体。(3)我们对于淋巴瘤细胞Bik水平检测提示四种淋巴瘤细胞的Bik表达水平不同程度地低于肝细胞的Bik水平。S-VISA-BikDD转染后能不同程度提高淋巴瘤细胞的Bik表达水平,并且对于淋巴瘤细胞Raji、Ramos、U937和Hut78具有明显的生长抑制作用,对淋巴瘤Raji细胞具有促凋亡作用。
结论：就淋巴瘤细胞和肝细胞而言,Survivin启动子能调控外源基因在淋巴瘤细胞中特异性表达,VISA系统能明显增强Survivin启动子的活性,使目的基因在淋巴瘤细胞中高效特异性表达S-VISA-BikDD能对淋巴瘤细胞造成明显的生长抑制作用及一定的凋亡诱导作用,S-VISA-BikDD是很有潜力的淋巴瘤基因治疗载体。
Bcl-2 family is one of the most important genes families to regulate apoptosis. Bcl-2 family contain anti-apoptotic family members (e.g. Bcl-XL、Bcl-2), and pro-apoptotic family members, such as Bik and Bax. The abnormality of Bcl-2 family not only relates to the genesis and progression of tumors, it also links to the chemosensitivity of some anticancer drugs. The low expression of pro-apoptotic family members or the over expression of anti-apoptotic family members in many lymphoma cells result in the insensitivity of inducing apoptosis as well as the resistance of chemotherapy for lymphoma cells. Bik is one of the most potent BH3-only proteins, shown to interact with more anti-apoptotic family members and have stronger binging force with widely studied Bcl-2 than others pro-apoptotic family members. Bik mutant (BikDD), in which changes were made in T33D and S35D to mimic phosphorylation at these two residues, can enhance its binding affinity with the antiapoptotic proteins Bcl-X1 and Bcl-2 and show more potent than wild-type bik in inducing apoptosis and inhibiting cell proliferation of cancer cells.
Transduction of BikDD gene into lymphoma cells may be a promising method of gene therapy for lymphoma. One of the major obstacles of gene therapy is that the ectopic gene cannot express highly in targeted cells. The objective of this study focuses on how to guarantee BikDD gene expresses highly in lymphoma cell lines and research the apoptotic effects of BikDD on lymphoma cell lines.
In the first part of this study, we generated luciferase vectors contain Survivin promoter, hTERT promoter and CMV promoter respectively. We detected the luciferase expression of vectors in different lymphoma cell lines and hepatic cell line chang liver to evaluate the efficacy and lymphoma specificity of promoters.
In the second part, we constructed three plasmids contained different elements of WPRE, TSTA and VISA under control of Survivin promoter. We detected the luciferase expression of vectors in different lymphoma cell lines and hepatic cell line to select the most efficient amplification system, which would be used to construct high efficient and lymphoma-specific gene expression vectors with Survivin promoter.
In the third part, the lymphoma cell lines Raji, Ramos, U937, hut78 and hepatic cell line chang liver were transfected with the recombinant BikDD vector, which contained a 987 bp human Survivin promoter, a mutant Bik cDNA, as a pro-apoptotic gene, and VISA signal amplification system. Then, Western blot was used to assess the different lymphoma cell lines expression of Bik. We also used the MTT assay and flow cytometry to detect growth inhibition and pro-apoptotic effects on lymphoma cell lines.
Results:The luciferase detection results showed that Survivin promoter was more efficient and lymphoma-specific than hTERT promoter. S-VISA and S-TSTA showed more efficient than pGL3-CMV in lymphoma cell lines Raji, Ramos, Hut78 and U937 (p<0.05), but less efficient than pGL3-CMV in hepatic cell line chang liver. S-VISA was selected as highly efficient and targeted gene expression vector in lymphoma cell lines for its higher efficacy in Raji, Ramos and U937 than S-TSTA (p<0.05)
Results of Western blot showed that Bik expression of lymphoma cells was lower than Bik expression in chang liver cells in different degree, and Bik expression increased in different degree after lymphoma cells were transfected with S-VISA-BikDD plasmid. S-VISA-BikDD resulted in significant growth inhibition in all transfected cell lines except chang liver. S-VISA-BikDD resulted in significant apoptosis in transfected Raji cell line.
Conclusion:So far as lymphoma cells and hepatic cells, the Survivin promoter can make Bik gene expressing targeted in lymphoma cells. VISA system amplifies the activity of Survivin promoter effectively. S-VISA-BikDD pro-apoptotic vector can lead the lymphoma cells to apoptosis and growth inhibition. S-VISA-BikDD is an effective pro-apoptotic vector for gene therapy in lymphoma.
引文
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