LRIG1对人脑胶质瘤细胞增殖及放疗敏感性的影响及其机制的研究
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摘要
目的：采用脂质体转染质粒的方法上调人脑胶质瘤细胞中LRIG1基因的表达,探讨LRIG1基因对人脑胶质瘤细胞细胞周期、凋亡率、DNA损伤修复、细胞增殖及放疗敏感性的影响及其可能的作用机制。
方法：通过脂质体介导的方法转染含有LRIG1基因的质粒进入人脑胶质瘤U251细胞,得到高表达LRIG1的瞬时转染细胞。通过G418筛选并建立稳定表达LRIG1的细胞株。采用Western Blot及RT-PCR方法检测细胞中LRIG1、P27、Bax、 Bcl-2及Rad51基因或蛋白表达的变化。CCK-8法测定细胞生长抑制率。细胞染色后流式细胞仪测定其细胞周期分布及凋亡率。克隆形成实验检测细胞放疗敏感性。彗星分析试验检测细胞放疗前后DNA损伤的修复。
结果：成功建立稳定表达LRIG1细胞株,荧光显微镜下可见细胞表达绿色荧光蛋白,其LRIG1蛋白表达量高于空载体对照组(P<0.05)。转染含LRIG1质粒后,人脑胶质瘤细胞LRIG1mRNA表达上调(P<0.05)。LRIG1基因显著抑制了人脑胶质瘤细胞的增殖,转染LRIG1基因72h后较未转染的U251细胞的细胞增殖抑制率为26.4%。LRIG1上调了细胞周期调控蛋白P27的表达(P<0.01),相对于对照组未转染细胞的处于GO/G1期的细胞比率(38.5±2.1)%, LRIG1高表达组处于GO/G1期的细胞比率增加到(61.2±3.1)%,差异具有统计学意义(P<0.01),从而LRIG1降低了细胞增殖指数。LRIG1上调了细胞中促凋亡蛋白Bax的表达(P<0.05),同时显著降低了凋亡抑制蛋白Bcl-2的表达(P<0.01), LRIG1高表达组的细胞凋亡率为(16.6±0.8)%,与对照组未转染细胞的(8.8±0.3)%相比,凋亡率显著增高(P<0.01)。而克隆形成实验证明LRIG1显著增强了人脑胶质瘤细胞的放疗敏感性,其放射增敏比为1.448。而在放疗前及放疗后LRIG1均显著抑制了细胞中DNA损伤修复蛋白Rad51的表达,其差异均具有统计学意义(P<0.01,P<0.01),而彗星分析显示放射治疗后LRIG1抑制了人脑胶质瘤细胞的DNA损伤修复(P<0.05)。
结论：实验成功建立了稳定表达LRIG1蛋白的人脑胶质瘤U251细胞系。LRIG1通过上调细胞周期调控蛋白P27的表达,上调处于GO/G1期的人脑胶质瘤细胞比率,从而抑制细胞生长。LRIG1通过调控凋亡相关蛋白Bax, Bcl-2的表达,促进人脑胶质瘤细胞凋亡。LRIG1可降低人脑胶质瘤细胞放射治疗前后DNA损伤修复蛋白Rad51的表达,从而降低放疗前后细胞DNA损伤的修复,最终导致细胞死亡。因此,LRIG1能够抑制人脑胶质瘤细胞生长并增强其放疗敏感性,对人脑胶质瘤具有治疗作用,实验为LRIG1应用于人脑胶质瘤临床治疗提供了新的依据。
Objective:To up-regulate LRIG1gene expression in human glioma cells with liposomal transfection. To investigate the effect and mechanism of LRIG1gene on the cell cycle, apoptosis, DNA repair, cell proliferation and radiosensitivity of human glioma cells.
Methods:Got the LRIG1overexpression human glioma U251cells by the method of liposome-mediated transiently transfection. Selected and set up a stable LRIG1overexpression cell line by G418. Detected the changes of LRIG1, P27, Bax, Bcl-2and Rad51expression in the cells with Western blot or RT-PCR. The cell growth inhibition rate was detected by CCK-8method. The cell cycle distribution and apoptosis rate were detected by flow cytometry after staining. The cell radiosensitivity was detected by clonogenic assay. The repairment of DNA damage before and after radiation were detected by comet assay method. Results:The LRIG1line was set up successfully. There was expression of green fluorescent protein in the LRIG1over-expression U251cells, observed by the fluorescence microscope. The expression of LRIG1protein in the stable LRIG1overexpression cell line was higher than the blank vector control cell line (P<0.05). Transiently transfected with plasmid encoding LRIG1protein, the expression of LRIG1mRNA in human glioma cells was increased (P<0.05). The over-expression of LRIG1significantly inhibited the proliferation of human glioma cells. After transfected with the LRIG1gene72hours, the inhibition rate of cell proliferation was up to26.4%. The over-expression of LRIG1up-regulated the expression of cell cycle inhibitor P27(P<0.01) and increasd the cell ratio of G0/G1phase from (38.5±2.1)%to (61.2±3.1)%(P<0.01). Thus the cell proliferation index was reduced by the over-expression of LRIG1. The over-expression of LRIG1increased the expression of pro-apoptotic protein Bax (P<0.05), while significantly reducd the expression of anti-apoptotic protein Bcl-2(P<0.01). Compared with (8.8±0.3)%of the control group, the cells apoptosis rate of the LRIG1over-expression group was up-regulated to (16.6±0.8)%(P<0.01). The radiosensitivity of human glioma cells was significantly enhanced by the over-expression of LRIG1in the clonogenic assay. The SER was1.448. DNA repair protein Rad51was significantly inhibited by LR1G1before and after radiation(P<0.01, P<0.01). The DNA damage repairment of human glioma cells was inhibited by LRIG1in the comet assay(P<0.05).
Conclusion:The human glioma U251cell line stably expressing LRIG1protein was successfully set up in the experiment. The cell cycle inhibitor P27was up-regulated by the LRIG1overexpression. The the ratio of human glioma cells in the G0/G1phase was increased, and then cell growth was inhibited. The overexpression of LRIG1promoted the apoptosis of human glioma cells by the up-regulation of pro-apoptotic protein Bax and the down-regulation of anti-apoptotic protein Bcl-2. The expression of DNA repair protein Rad51was inhibited by the overexpression of LR1G1in human glioma cells before and after radiation, and then the repairment of DNA damage before and after radiotherapy was down-regulated. In summary, LRIG1can suppress the proliferation and enhance the radiosensitivity of human glioma cells. The research provided new evidences for the clinical application of LRIG1treating human gliomas.
方法：通过脂质体介导的方法转染含有LRIG1基因的质粒进入人脑胶质瘤U251细胞,得到高表达LRIG1的瞬时转染细胞。通过G418筛选并建立稳定表达LRIG1的细胞株。采用Western Blot及RT-PCR方法检测细胞中LRIG1、P27、Bax、 Bcl-2及Rad51基因或蛋白表达的变化。CCK-8法测定细胞生长抑制率。细胞染色后流式细胞仪测定其细胞周期分布及凋亡率。克隆形成实验检测细胞放疗敏感性。彗星分析试验检测细胞放疗前后DNA损伤的修复。
结果：成功建立稳定表达LRIG1细胞株,荧光显微镜下可见细胞表达绿色荧光蛋白,其LRIG1蛋白表达量高于空载体对照组(P<0.05)。转染含LRIG1质粒后,人脑胶质瘤细胞LRIG1mRNA表达上调(P<0.05)。LRIG1基因显著抑制了人脑胶质瘤细胞的增殖,转染LRIG1基因72h后较未转染的U251细胞的细胞增殖抑制率为26.4%。LRIG1上调了细胞周期调控蛋白P27的表达(P<0.01),相对于对照组未转染细胞的处于GO/G1期的细胞比率(38.5±2.1)%, LRIG1高表达组处于GO/G1期的细胞比率增加到(61.2±3.1)%,差异具有统计学意义(P<0.01),从而LRIG1降低了细胞增殖指数。LRIG1上调了细胞中促凋亡蛋白Bax的表达(P<0.05),同时显著降低了凋亡抑制蛋白Bcl-2的表达(P<0.01), LRIG1高表达组的细胞凋亡率为(16.6±0.8)%,与对照组未转染细胞的(8.8±0.3)%相比,凋亡率显著增高(P<0.01)。而克隆形成实验证明LRIG1显著增强了人脑胶质瘤细胞的放疗敏感性,其放射增敏比为1.448。而在放疗前及放疗后LRIG1均显著抑制了细胞中DNA损伤修复蛋白Rad51的表达,其差异均具有统计学意义(P<0.01,P<0.01),而彗星分析显示放射治疗后LRIG1抑制了人脑胶质瘤细胞的DNA损伤修复(P<0.05)。
结论：实验成功建立了稳定表达LRIG1蛋白的人脑胶质瘤U251细胞系。LRIG1通过上调细胞周期调控蛋白P27的表达,上调处于GO/G1期的人脑胶质瘤细胞比率,从而抑制细胞生长。LRIG1通过调控凋亡相关蛋白Bax, Bcl-2的表达,促进人脑胶质瘤细胞凋亡。LRIG1可降低人脑胶质瘤细胞放射治疗前后DNA损伤修复蛋白Rad51的表达,从而降低放疗前后细胞DNA损伤的修复,最终导致细胞死亡。因此,LRIG1能够抑制人脑胶质瘤细胞生长并增强其放疗敏感性,对人脑胶质瘤具有治疗作用,实验为LRIG1应用于人脑胶质瘤临床治疗提供了新的依据。
Objective:To up-regulate LRIG1gene expression in human glioma cells with liposomal transfection. To investigate the effect and mechanism of LRIG1gene on the cell cycle, apoptosis, DNA repair, cell proliferation and radiosensitivity of human glioma cells.
Methods:Got the LRIG1overexpression human glioma U251cells by the method of liposome-mediated transiently transfection. Selected and set up a stable LRIG1overexpression cell line by G418. Detected the changes of LRIG1, P27, Bax, Bcl-2and Rad51expression in the cells with Western blot or RT-PCR. The cell growth inhibition rate was detected by CCK-8method. The cell cycle distribution and apoptosis rate were detected by flow cytometry after staining. The cell radiosensitivity was detected by clonogenic assay. The repairment of DNA damage before and after radiation were detected by comet assay method. Results:The LRIG1line was set up successfully. There was expression of green fluorescent protein in the LRIG1over-expression U251cells, observed by the fluorescence microscope. The expression of LRIG1protein in the stable LRIG1overexpression cell line was higher than the blank vector control cell line (P<0.05). Transiently transfected with plasmid encoding LRIG1protein, the expression of LRIG1mRNA in human glioma cells was increased (P<0.05). The over-expression of LRIG1significantly inhibited the proliferation of human glioma cells. After transfected with the LRIG1gene72hours, the inhibition rate of cell proliferation was up to26.4%. The over-expression of LRIG1up-regulated the expression of cell cycle inhibitor P27(P<0.01) and increasd the cell ratio of G0/G1phase from (38.5±2.1)%to (61.2±3.1)%(P<0.01). Thus the cell proliferation index was reduced by the over-expression of LRIG1. The over-expression of LRIG1increased the expression of pro-apoptotic protein Bax (P<0.05), while significantly reducd the expression of anti-apoptotic protein Bcl-2(P<0.01). Compared with (8.8±0.3)%of the control group, the cells apoptosis rate of the LRIG1over-expression group was up-regulated to (16.6±0.8)%(P<0.01). The radiosensitivity of human glioma cells was significantly enhanced by the over-expression of LRIG1in the clonogenic assay. The SER was1.448. DNA repair protein Rad51was significantly inhibited by LR1G1before and after radiation(P<0.01, P<0.01). The DNA damage repairment of human glioma cells was inhibited by LRIG1in the comet assay(P<0.05).
Conclusion:The human glioma U251cell line stably expressing LRIG1protein was successfully set up in the experiment. The cell cycle inhibitor P27was up-regulated by the LRIG1overexpression. The the ratio of human glioma cells in the G0/G1phase was increased, and then cell growth was inhibited. The overexpression of LRIG1promoted the apoptosis of human glioma cells by the up-regulation of pro-apoptotic protein Bax and the down-regulation of anti-apoptotic protein Bcl-2. The expression of DNA repair protein Rad51was inhibited by the overexpression of LR1G1in human glioma cells before and after radiation, and then the repairment of DNA damage before and after radiotherapy was down-regulated. In summary, LRIG1can suppress the proliferation and enhance the radiosensitivity of human glioma cells. The research provided new evidences for the clinical application of LRIG1treating human gliomas.
引文
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