β1，3-N-乙酰氨基葡萄糖基转移酶（β3Gn-T8）对人脑星形胶质瘤侵袭和增殖的影响
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摘要
本研究旨在探讨β1，3-N-乙酰氨基葡萄糖基转移酶8（β3Gn-T8）对胶质瘤侵袭及增殖的影响。通过对胶质瘤细胞恶性表型相关因子、成瘤模型及临床标本的相关指标检测分析，来了解β3Gn-T8在胶质瘤的发生发展中扮演的重要作用，为治疗人恶性胶质瘤提供一个新的有效的辅助分子治疗方法。
目的：
（1）探讨糖基转移酶β3Gn-T8在人脑胶质瘤组织与正常脑组织中表达的差异。
（2）在人胶质瘤U251细胞水平探讨糖基转移酶β3Gn-T8对胶质瘤侵袭及增殖能力的影响，以及β3Gn-T8与MMP-2的关系。
（3）观察糖基转移酶β3Gn-T8对胶质瘤U251细胞裸鼠皮下种植瘤生长的影响。
（4）探讨糖基转移酶β3Gn-T8对肿瘤细胞多聚乳糖胺链的影响。
方法：
（1）运用免疫组织化学方法，在人脑星形胶质瘤和正常脑组织的石蜡标本上，分别检测β3Gn-T8的表达情况并分析其差异。收集相关胶质瘤组织标本的临床病理参数，通过统计学方法分析胶质瘤β3Gn-T8表达与临床病理参数的关系。
（2）将β3Gn-T8的真核表达正义载体pEGFP-C1-T8及空载体pEGFP-C1、RNA干扰载体pSilenCircle-T8Si及对照载体pSilenCircle-T8Scr，通过脂质体转入人星形胶质瘤U251细胞，经G418筛选出稳定细胞株，RT-PCR挑选出上调、下调β3Gn-T8最优的细胞株。将细胞分为五组：U251转染正义载体组（T8S）与空载体组（Mock）、U251转染干扰载体组（T8Si）与对照载体组（T8Scr）、U251未转染组（NC）。RT-PCR、Western blot及免疫荧光检测五组细胞β3Gn-T8的表达，并用流式细胞术分析β3Gn-T8高/低表达细胞株的多聚乳糖胺链的变化。
（3）在体外实验中，通过MTT检测以上各组细胞生长状况，集落形成实验检测各组细胞单细胞形成集落的能力；Boyden小室和划痕修复实验检测各组细胞侵袭迁移能力差异；采用RT-PCR及Western blot方法检测以上五组细胞的MMP-2、TIMP-2mRNA及蛋白水平表达变化。
（4）在体内实验中，将转染正义载体组（T8S）、干扰载体组（T8Si）及未转染组（NC）的U251细胞通过皮下接种BALB/c裸鼠的方法构建胶质瘤移植瘤模型。通过对移植瘤成瘤时间、生长曲线和最终体积指标的测量以及病理学观察，探讨β3Gn-T8对胶质瘤移植瘤增殖和侵袭能力的影响。
结果：
（1）临床人脑星形胶质瘤组织中β3Gn-T8蛋白表达阳性率为88.10﹪，显著高于正常脑组织12.5﹪（P﹤0.01），且β3Gn-T8蛋白的表达与胶质瘤的临床病理分级正相关（P﹤0.05）。
（2）通过RT-PCR和Western blot的检测，以及激光共聚焦显微镜观察各组细胞，可见载体成功转入人星形胶质瘤U251细胞，得到稳定转染细胞株。同时，流式细胞术显示，上调β3Gn-T8的表达水平，多聚乳糖胺链产量增加，下调β3Gn-T8的表达水平，多聚乳糖胺链产量减少。
（3）对转染pEGFP-C1-T8的U251细胞进行侵袭和增殖能力的系列检测，和空载体组相比较，MTT检测显示细胞的增殖能力升高（P﹤0.05），集落形成实验显示细胞集落形成能力增强；Boyden小室实验和划痕修复实验发现细胞的侵袭迁移能力增强（P﹤0.05）；RT-PCR及Western blot检测发现MMP-2的表达在mRNA水平及蛋白水平相应升高（P﹤0.05），而TIMP-2的表达不存在统计学意义。
对转染pSilenCircle-T8Si的U251细胞进行侵袭和增殖能力的系列检测，和对照载体组相比较，MTT检测显示细胞的增殖能力下降（P﹤0.05），集落形成实验显示细胞集落数明显降低；Boyden小室实验发现细胞穿膜率较低，侵袭能力弱（P﹤0.05），划痕修复实验显示细胞划痕修复较慢，迁移能力下降（P﹤0.05）；RT-PCR及Western blot检测发现MMP-2的表达在mRNA水平及蛋白水平相应降低（P﹤0.05），而TIMP-2的表达不存在统计学意义。
（4）人星形胶质瘤U251细胞裸鼠移植瘤成瘤率100﹪。与NC组相比，T8S组移植瘤成瘤时间较短，生长速度较快，最终体积更大（P﹤0.05）；T8Si组移植瘤成瘤时间延长，其生长速度和最终体积均小于NC组（P﹤0.05）。移植瘤组织学呈现典型的恶性肿瘤细胞形态特点，且T8S组的移植瘤细胞向周围肌肉组织侵袭生长。
结论：
（1） β3Gn-T8在人星形胶质瘤组织的表达较正常脑组织显著增加，其表达与胶质瘤的临床病理分级正相关。
（2）成功构建了稳定的β3Gn-T8上调及下调细胞株。
（3） β3Gn-T8促进了多聚乳糖胺链的合成。
（4） β3Gn-T8增强了人星形胶质瘤U251细胞的增殖和侵袭能力。
（5）在细胞水平，随着β3Gn-T8表达的上调，MMP-2的表达也相应升高，而TIMP-2表达水平不存在统计学意义。β3Gn-T8可能通过促使多聚乳糖胺链的合成，影响MMP-2/TIMP-2比值，打乱了两者间的平衡，而促进了U251细胞的增殖和侵袭能力。
（6） β3Gn-T8增强了胶质瘤裸鼠移植瘤的增殖和侵袭能力。
综上所述，糖基转移酶β3Gn-T8在人胶质瘤组织的表达与胶质瘤的临床病理分级正相关；糖基转移酶β3Gn-T8对胶质瘤细胞的增殖和侵袭能力有增强作用；糖基转移酶β3Gn-T8对胶质瘤细胞中的MMP-2的表达具有调控作用，推测这可能是促进胶质瘤侵袭的机制之一。
Objective:
(1) To investigate the difference of β3Gn-T8protein expression in astrogliomatissue and normal brain tissues.
(2) To investigate proliferating and invasion regulation of glioma by β3Gn-T8inhuman astroglioma cell lines U251and subcutaneous glioma of nude mice.
(3) To investigate the relationship between β3Gn-T8and MMP-2.
(4) To investigate the effect of β3Gn-T8on Biosynthesis of polylactosamines.
Methods:
(1) Detected the expression of β3Gn-T8on human astroglioma and normal braintissues by immunohistochemistry. Collected clinical and pathological parameters of42cases of astroglioma and analyzed the correlation of β3Gn-T8expression withclinicopathological parameters.
(2) β3Gn-T8sense vector and its empty vector, β3Gn-T8RNA interference vectorand its control vector were transfected stably into U251cells by Liprofectamine2000.And the stably transfected cell lines were sieved by G418. The optimal cell lines ofβ3Gn-T8upregulation and knockdown were chosed by RT-PCR. There were fivegroups: U251transfected with sense vector and empty vector groups, U251transfectedwith interference vector and control vector groups, U251non-tranfected group. AndRT-PCR, Western blot and Laser Confocal Microscope were used to compare theexpression of β3Gn-T8in the five group cell lines. U251cells transfected withpEGFP-C1-T8or pSilenCircle-T8Si were examined for changes in the cell surfaceexpression of carbohydrate chains by flow cytometric analysis.
(3) MTT was used to detect the cell proliferation, and colony formation assay wasused to evaluate the ability of colony formation from single cell in different groups. Wound healing and Boyden chamber were used to compare the ability of cell migrationand invasion in five groups. RT-PCR and Western blot were used to evaluate thevariational characteristics of MMP-2and TIMP-2expression at mRNA and proteinlevel.
(4) Constructed model of glioma via subcutaneous inoculation transfected U251cells of pSilenCircle-T8Si and pEGFP-C1-T8to nude mouse. By the time of tumorformation, growth curves and tumor size were detected to research the effect ofβ3Gn-T8on proliferation of glioma. Detected the effect of β3Gn-T8on the invasiveability of glioma of nude mice by HE staining.
Results:
(1) β3Gn-T8expression in astroglioma tissues was significantly higher than innormal brain tissues (P﹤0.01), and with increasing depth of higher clinical stage,β3Gn-T8expression was increased (P﹤0.05);
(2) Vectors were transfected into cells successfully, which was observed throughRT-PCR, Western blot and Laser Confocal Microscope. And we got the stablytransfected cell lines whose β3Gn-T8expressions were upregulated and knockdown.The biosynthesis of polylactosamine chains was decreased in pSilenCircle-T8Si cells，while increased in pEGFP-C1-T8cells.
(3) MTT assay showed cell proliferation was higher in over-expressing β3Gn-T8cells than control. And cells with β3Gn-T8knockdown had a poor ability ofproliferation (P﹤0.05). The over-expression β3Gn-T8cells formed more colonies thanthe cells thansfected with empty vetors. And the knockdown of β3GnT8cells formedletter colonies than the control cells (P﹤0.05).
Compared to control, over-expression of β3Gn-T8promoted the invasion of U251cells while knock-down of β3Gn-T8inhibited U251cell invasion. Furthermore, woundhealing was performed to investigate the effect of β3Gn-T8on U251cell migration.Consistent with the results of the Boyden chamber assay, over-expression of β3Gn-T8enhanced cell migration (P﹤0.05) in vitro, while knockdown of β3Gn-T8inhibited themigration (P﹤0.05) of U251cells.
Our results showed that the expression of MMP-2increased in β3Gn-T8over-expression cells, and decreased in β3Gn-T8knockdown cells both in mRNA and protein levels. But the expression of TIMP-2had no statistical significance in mRNAand protein levels.
(4) Glioma model of nude mice was constructed successfully, the tumor form ratewas100%. The forming rate and volume of tumor of nude mice in pSilenCircle-T8Sigroup were significantly smaller than the control group (P﹤0.05); on the contrary side,those except the forming time in pEGFP-C1-T8group were significantly higher than thecontrol group (P﹤0.05). And pEGFP-C1-T8group showed tumor invasion of thesurrounding muscle.
Conclusion:
(1) β3Gn-T8expression in human astroglioma was increased, and β3Gn-T8expression in human glioma was positive correlated with clinical stage of glioma.
(2) The stable upregulation and downregulation of β3Gn-T8U251cells wereestablished
(3) The result indicated that β3Gn-T8is involved in the biosynthesis ofpolylactosamine chains
(4) β3Gn-T8can promoted the invasion and proliferation of U251glioma cells.Up-regulation of β3Gn-T8increased the mRNA and protein expression of MMP-2.Down-regulation cells showed opposite results. But the expression of TIMP-2had nostatistical significance in mRNA and protein levels. Therefore, these results suggestedthat β3Gn-T8might affect the balance of MMP-2and TIMP-2, and then promote cellmigration and invasion.
(5) β3Gn-T8can promote the proliferation and invasion of glioma xenografts innude mice.
Therefore, our findings indicated that β3Gn-T8might play a role in cellproliferation and invasion in glioma, indicating a new adjuvant molecular therapystrategy to effective therapy of human malignant glioma.
目的：
（1）探讨糖基转移酶β3Gn-T8在人脑胶质瘤组织与正常脑组织中表达的差异。
（2）在人胶质瘤U251细胞水平探讨糖基转移酶β3Gn-T8对胶质瘤侵袭及增殖能力的影响，以及β3Gn-T8与MMP-2的关系。
（3）观察糖基转移酶β3Gn-T8对胶质瘤U251细胞裸鼠皮下种植瘤生长的影响。
（4）探讨糖基转移酶β3Gn-T8对肿瘤细胞多聚乳糖胺链的影响。
方法：
（1）运用免疫组织化学方法，在人脑星形胶质瘤和正常脑组织的石蜡标本上，分别检测β3Gn-T8的表达情况并分析其差异。收集相关胶质瘤组织标本的临床病理参数，通过统计学方法分析胶质瘤β3Gn-T8表达与临床病理参数的关系。
（2）将β3Gn-T8的真核表达正义载体pEGFP-C1-T8及空载体pEGFP-C1、RNA干扰载体pSilenCircle-T8Si及对照载体pSilenCircle-T8Scr，通过脂质体转入人星形胶质瘤U251细胞，经G418筛选出稳定细胞株，RT-PCR挑选出上调、下调β3Gn-T8最优的细胞株。将细胞分为五组：U251转染正义载体组（T8S）与空载体组（Mock）、U251转染干扰载体组（T8Si）与对照载体组（T8Scr）、U251未转染组（NC）。RT-PCR、Western blot及免疫荧光检测五组细胞β3Gn-T8的表达，并用流式细胞术分析β3Gn-T8高/低表达细胞株的多聚乳糖胺链的变化。
（3）在体外实验中，通过MTT检测以上各组细胞生长状况，集落形成实验检测各组细胞单细胞形成集落的能力；Boyden小室和划痕修复实验检测各组细胞侵袭迁移能力差异；采用RT-PCR及Western blot方法检测以上五组细胞的MMP-2、TIMP-2mRNA及蛋白水平表达变化。
（4）在体内实验中，将转染正义载体组（T8S）、干扰载体组（T8Si）及未转染组（NC）的U251细胞通过皮下接种BALB/c裸鼠的方法构建胶质瘤移植瘤模型。通过对移植瘤成瘤时间、生长曲线和最终体积指标的测量以及病理学观察，探讨β3Gn-T8对胶质瘤移植瘤增殖和侵袭能力的影响。
结果：
（1）临床人脑星形胶质瘤组织中β3Gn-T8蛋白表达阳性率为88.10﹪，显著高于正常脑组织12.5﹪（P﹤0.01），且β3Gn-T8蛋白的表达与胶质瘤的临床病理分级正相关（P﹤0.05）。
（2）通过RT-PCR和Western blot的检测，以及激光共聚焦显微镜观察各组细胞，可见载体成功转入人星形胶质瘤U251细胞，得到稳定转染细胞株。同时，流式细胞术显示，上调β3Gn-T8的表达水平，多聚乳糖胺链产量增加，下调β3Gn-T8的表达水平，多聚乳糖胺链产量减少。
（3）对转染pEGFP-C1-T8的U251细胞进行侵袭和增殖能力的系列检测，和空载体组相比较，MTT检测显示细胞的增殖能力升高（P﹤0.05），集落形成实验显示细胞集落形成能力增强；Boyden小室实验和划痕修复实验发现细胞的侵袭迁移能力增强（P﹤0.05）；RT-PCR及Western blot检测发现MMP-2的表达在mRNA水平及蛋白水平相应升高（P﹤0.05），而TIMP-2的表达不存在统计学意义。
对转染pSilenCircle-T8Si的U251细胞进行侵袭和增殖能力的系列检测，和对照载体组相比较，MTT检测显示细胞的增殖能力下降（P﹤0.05），集落形成实验显示细胞集落数明显降低；Boyden小室实验发现细胞穿膜率较低，侵袭能力弱（P﹤0.05），划痕修复实验显示细胞划痕修复较慢，迁移能力下降（P﹤0.05）；RT-PCR及Western blot检测发现MMP-2的表达在mRNA水平及蛋白水平相应降低（P﹤0.05），而TIMP-2的表达不存在统计学意义。
（4）人星形胶质瘤U251细胞裸鼠移植瘤成瘤率100﹪。与NC组相比，T8S组移植瘤成瘤时间较短，生长速度较快，最终体积更大（P﹤0.05）；T8Si组移植瘤成瘤时间延长，其生长速度和最终体积均小于NC组（P﹤0.05）。移植瘤组织学呈现典型的恶性肿瘤细胞形态特点，且T8S组的移植瘤细胞向周围肌肉组织侵袭生长。
结论：
（1） β3Gn-T8在人星形胶质瘤组织的表达较正常脑组织显著增加，其表达与胶质瘤的临床病理分级正相关。
（2）成功构建了稳定的β3Gn-T8上调及下调细胞株。
（3） β3Gn-T8促进了多聚乳糖胺链的合成。
（4） β3Gn-T8增强了人星形胶质瘤U251细胞的增殖和侵袭能力。
（5）在细胞水平，随着β3Gn-T8表达的上调，MMP-2的表达也相应升高，而TIMP-2表达水平不存在统计学意义。β3Gn-T8可能通过促使多聚乳糖胺链的合成，影响MMP-2/TIMP-2比值，打乱了两者间的平衡，而促进了U251细胞的增殖和侵袭能力。
（6） β3Gn-T8增强了胶质瘤裸鼠移植瘤的增殖和侵袭能力。
综上所述，糖基转移酶β3Gn-T8在人胶质瘤组织的表达与胶质瘤的临床病理分级正相关；糖基转移酶β3Gn-T8对胶质瘤细胞的增殖和侵袭能力有增强作用；糖基转移酶β3Gn-T8对胶质瘤细胞中的MMP-2的表达具有调控作用，推测这可能是促进胶质瘤侵袭的机制之一。
Objective:
(1) To investigate the difference of β3Gn-T8protein expression in astrogliomatissue and normal brain tissues.
(2) To investigate proliferating and invasion regulation of glioma by β3Gn-T8inhuman astroglioma cell lines U251and subcutaneous glioma of nude mice.
(3) To investigate the relationship between β3Gn-T8and MMP-2.
(4) To investigate the effect of β3Gn-T8on Biosynthesis of polylactosamines.
Methods:
(1) Detected the expression of β3Gn-T8on human astroglioma and normal braintissues by immunohistochemistry. Collected clinical and pathological parameters of42cases of astroglioma and analyzed the correlation of β3Gn-T8expression withclinicopathological parameters.
(2) β3Gn-T8sense vector and its empty vector, β3Gn-T8RNA interference vectorand its control vector were transfected stably into U251cells by Liprofectamine2000.And the stably transfected cell lines were sieved by G418. The optimal cell lines ofβ3Gn-T8upregulation and knockdown were chosed by RT-PCR. There were fivegroups: U251transfected with sense vector and empty vector groups, U251transfectedwith interference vector and control vector groups, U251non-tranfected group. AndRT-PCR, Western blot and Laser Confocal Microscope were used to compare theexpression of β3Gn-T8in the five group cell lines. U251cells transfected withpEGFP-C1-T8or pSilenCircle-T8Si were examined for changes in the cell surfaceexpression of carbohydrate chains by flow cytometric analysis.
(3) MTT was used to detect the cell proliferation, and colony formation assay wasused to evaluate the ability of colony formation from single cell in different groups. Wound healing and Boyden chamber were used to compare the ability of cell migrationand invasion in five groups. RT-PCR and Western blot were used to evaluate thevariational characteristics of MMP-2and TIMP-2expression at mRNA and proteinlevel.
(4) Constructed model of glioma via subcutaneous inoculation transfected U251cells of pSilenCircle-T8Si and pEGFP-C1-T8to nude mouse. By the time of tumorformation, growth curves and tumor size were detected to research the effect ofβ3Gn-T8on proliferation of glioma. Detected the effect of β3Gn-T8on the invasiveability of glioma of nude mice by HE staining.
Results:
(1) β3Gn-T8expression in astroglioma tissues was significantly higher than innormal brain tissues (P﹤0.01), and with increasing depth of higher clinical stage,β3Gn-T8expression was increased (P﹤0.05);
(2) Vectors were transfected into cells successfully, which was observed throughRT-PCR, Western blot and Laser Confocal Microscope. And we got the stablytransfected cell lines whose β3Gn-T8expressions were upregulated and knockdown.The biosynthesis of polylactosamine chains was decreased in pSilenCircle-T8Si cells，while increased in pEGFP-C1-T8cells.
(3) MTT assay showed cell proliferation was higher in over-expressing β3Gn-T8cells than control. And cells with β3Gn-T8knockdown had a poor ability ofproliferation (P﹤0.05). The over-expression β3Gn-T8cells formed more colonies thanthe cells thansfected with empty vetors. And the knockdown of β3GnT8cells formedletter colonies than the control cells (P﹤0.05).
Compared to control, over-expression of β3Gn-T8promoted the invasion of U251cells while knock-down of β3Gn-T8inhibited U251cell invasion. Furthermore, woundhealing was performed to investigate the effect of β3Gn-T8on U251cell migration.Consistent with the results of the Boyden chamber assay, over-expression of β3Gn-T8enhanced cell migration (P﹤0.05) in vitro, while knockdown of β3Gn-T8inhibited themigration (P﹤0.05) of U251cells.
Our results showed that the expression of MMP-2increased in β3Gn-T8over-expression cells, and decreased in β3Gn-T8knockdown cells both in mRNA and protein levels. But the expression of TIMP-2had no statistical significance in mRNAand protein levels.
(4) Glioma model of nude mice was constructed successfully, the tumor form ratewas100%. The forming rate and volume of tumor of nude mice in pSilenCircle-T8Sigroup were significantly smaller than the control group (P﹤0.05); on the contrary side,those except the forming time in pEGFP-C1-T8group were significantly higher than thecontrol group (P﹤0.05). And pEGFP-C1-T8group showed tumor invasion of thesurrounding muscle.
Conclusion:
(1) β3Gn-T8expression in human astroglioma was increased, and β3Gn-T8expression in human glioma was positive correlated with clinical stage of glioma.
(2) The stable upregulation and downregulation of β3Gn-T8U251cells wereestablished
(3) The result indicated that β3Gn-T8is involved in the biosynthesis ofpolylactosamine chains
(4) β3Gn-T8can promoted the invasion and proliferation of U251glioma cells.Up-regulation of β3Gn-T8increased the mRNA and protein expression of MMP-2.Down-regulation cells showed opposite results. But the expression of TIMP-2had nostatistical significance in mRNA and protein levels. Therefore, these results suggestedthat β3Gn-T8might affect the balance of MMP-2and TIMP-2, and then promote cellmigration and invasion.
(5) β3Gn-T8can promote the proliferation and invasion of glioma xenografts innude mice.
Therefore, our findings indicated that β3Gn-T8might play a role in cellproliferation and invasion in glioma, indicating a new adjuvant molecular therapystrategy to effective therapy of human malignant glioma.
引文
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