Ezrin影响U251和U87细胞的侵袭性生长能力
摘要
脑胶质瘤是发生于神经外胚层的肿瘤，是最常见的原发性颅内肿瘤，其发病率、死亡率最高，发病率为3～10/10万，占颅内肿瘤的46%，占全身恶性肿瘤的1%～3%，5年存活率为20%～30%，是中枢神经系统疾病的难点。手术切除和放射治疗(RT)辅以化疗是当前治疗标准，但神经胶质瘤对治疗抵抗，也使得神经胶质瘤的预后极差，平均生存期为12到15个月。虽然近年神经影像学和术中肿瘤示踪技术的发展与应用，使神经胶质瘤的治疗取得了一定的进展，但也难以保证以手术为主的治疗能完全根除肿瘤，其根本原因是脑胶质瘤的生长特点造成的。
近年针对神经胶质瘤的分子靶标研制、开发了靶向治疗药物，临床试验有一定的治疗效果，但远未达到预期结果。此外，尽管科学工作者对肿瘤侵袭性生长的机制进行了大量研究，仍然不能深入了解脑胶质瘤浸润性生长的机制，因此深入研究其机制，寻找到其有效治疗的途径，是治疗神经胶质瘤、提高患者生存质量的关键。
肿瘤转移是恶性肿瘤的生物学特点，细胞运动能力增强导致其迁移和侵袭，细胞骨架的重塑是直接原因，而Ezrin是肌动蛋白与细胞膜及膜表面受体连接的桥梁，参与多种肌动蛋白的功能如细胞粘附，细胞运动和形态发生。在多种肿瘤组织表达上调，包括脑胶质瘤。但Ezrin在胶质瘤浸润性生长中的作用不清楚。
结合脑胶质瘤的生物学特性、治疗现状和Ezrin基因在肿瘤迁移和侵袭中的作用，本文研究了Ezrin与胶质瘤细胞U251和U87浸润性生长的相关性，并对其机制进行了探讨，主要研究结果：
1、成功构建Ezrin基因的shRNA表达载体，以脂质体Lipofectimine2000介导转染U87细胞，RT-PCR和Western blot检测结果表明，shRNA-Ezrin-2可沉默Ezrin表达，使其mRNA和蛋白表达量降低，确定为有效shRNA载体。
2、成功构建Ezrin基因表达载体pEGFP-C1/Ezrin。Western blot检测重组载体pEGFP-C1/Ezrin转染组Ezrin表达量高于空载体pEGFP-C1转染组和空白对照组。
3、shRNA-Ezrin-2与过表达载体pEGFP-C1/Ezrin分别转染U251和U87细胞，划痕试验结果显示Ezrin shRNA可阻断U251和U87细胞迁移，其过表达可促进细胞迁移。裸鼠脑瘤模型结果显示，与对照组对比，转染shRNA-Ezrin-2的细胞迁移数少，而转染pEGFP-C1/Ezrin的细胞迁移数相对较多，表明Ezrin基因沉默可阻断U251和U87细胞浸润性生长，过表达可促进迁移，增强其浸润生长，由此判断Ezrin参与U251和U87细胞浸润性生长。
4、为探讨Ezrin影响U251和U87细胞迁移、浸润性生长的机制，RT-PCR和Western blot分析shRNA-Ezrin-2与过表达载体pEGFP-C1/Ezrin转染细胞的Rac1的表达，结果显示，pEGFP-C1/Ezrin转染组Rac1表达量高于shRNA-Ezrin-2转染组和对照组，而shRNA-Ezrin-2转染组低于对照组。表明Ezrin可激活Rac1，Ezrin对U251和U87细胞的影响是通过Rac1实现的。
5、Transwell发现U87细胞的迁移能力强于U251细胞，为分析这种差异的原因，对Ezrin结构进行了分析，结果显示，U87细胞的Ezrin蛋白在第66、258、265和577位发生变异，而C端的34氨基酸是Ezrin与F-actin结合的位点，N端的296个氨基酸是与C端107个氨基酸残基相联系的功能域[22]，在此区域内发生氨基酸变异，是否影响Ezrin与F-actin或细胞膜的结合而影响其功能，从而影响细胞的迁移。本研究对具有不同浸润能力的脑胶质瘤细胞U251和U87的Ezrin蛋白功能和结构通过生物信息学方法加以分析、说明。Ezrin的蛋白功能分析显示，与U251细胞Ezrin“matched”的蛋白有362个，与U87细胞Ezrin“matched”的蛋白却有1503个；Ezrin的结构分析显示，U87细胞Ezrin的PDB多于U251细胞的，而SCOP和CATH所显示的结构域的结构分级和分层分级相同；U87细胞Ezrin的“Domain organisation”有45个，而U251细胞的Ezrin只有5个。SWISS-MODEL进一步分析，Coloring by residue error，U87细胞Ezrin有8处与U251细胞的不同，QMEAN4评分U87细胞Ezrin低于U251细胞的；SWISS-PDBViewer显示第258、265位氨基酸相对位于空间结构的内侧。推测U87细胞Ezrin的功能、结构域及空间结构均不同于U251细胞，导致了U251和U87细胞的迁移和浸润能力不同。
6、为验证Ezrin蛋白结构的差异造成U251和U87细胞迁移和浸润能力不同，本研究将U251细胞的Ezrin转染U87细胞，再将U87细胞的转染U251细胞，结果显示pEGFP-C1/Ezrin87转染的U251细胞大量迁移至伤口，伤口愈合较快，而转染pEGFP-C1/Ezrin251的U87细胞迁移的细胞数少于pEGFP-C1/Ezrin87转染组，伤口愈合较慢。裸鼠脑瘤动物模型也证实了这种结果。Rac1的表达量也与这种结果吻合。表明Ezrin可造成U251和U87细胞迁移、侵袭能力不同，且通过激活Rac1实现的。
Glioma is the tumor in the neural ectoderm, is the most common type of primaryintracranial tumors, it has high incidence and mortality, the rate of incidence is3~10per100thousand, accounted for46%of all intracranial tumors,1%~3%of systemicmalignant tumors,5-year survival rate is20%~30%[12]，and is a difficulty pointsfor the central nervous system diseases. Surgical resection and radiotherapy (RT),supplemented by chemotherapy is the current treatment standard, but gliomatreatment resistance, making very poor prognosis in glioma, average age12-15months[2-4]. Although in recent years, with the development and application of neuralimaging and intraoperative tumor tracer technology, it makes progress in the treatmentof glioma, but also difficult to ensure that predominantly surgical treatment cancompletely eradicate the tumor, the basic reason is the growth of gliomacharacteristics.
Recent years base on the research of gliomas molecular targets, targeted therapydrugs the development, clinical trial has certain therapeutic effect, but far fromexpected results. Moreover, although workers have done many studies on themechanism of invasive tumor growth, but still can't solve the mechanism of gliomainvasive growth, so further study of the mechanism and finding the effective way oftreatment, is the key to treatment of glioma and improve the quality of survival.
Tumor metastasis is the biological characteristics of malignant tumor, cellmovement ability enhanced lead to the migration and invasion, cytoskeletonremodeling is a direct reason, and Ezrin is actin bridge connected to the cellmembrane and membrane surface receptor[18], involved in many kinds of actinfunctions such as cell adhesion[20], cell movement and morphogenesis[21].Up-regulated the expression of variety of tumor tissue[8-15], including glioma. But therole of Ezrin in infiltrating growth of gliomas is not clear.
Combine with the current situation of biological characteristics, treatment ofglioma and the role of Ezrin genes in tumor migration and invasion, this paper studiesthe relationship of invasive growth between Ezrin and glioma cells U87、U251, and discuss the mechanism. The main research results:
1.The shRNA’s expression vector of Ezrin gene was constructed successfully,and U87cells were transfected by liposomes Lipofectimine2000, RT-PCR andWestern blot results showed that shRNA-Ezrin-2can be used to be silent theexpression of Ezrin, and made the expression levels of mRNA and protein decreased,it was identified to be valid shRNA vector.
2. The pEGFP-C1/Ezrin that was the expression vector of Ezrin gene wasconstructed successfully. Western blot detect the recombinant vector pEGFP-C1/Ezrinturn transfection group that Ezrin expression levels was higher than the empty vectorpEGFP-C1transfection group and blank control group.
3. After U87cells were transfected by shRNA vectors and expression vectors ofEzrin gene respectively, scratch experiments show that Ezrin shRNA can block themigration of U251and U87cells, and its over-expression can promote the cellmigration. The result of Brain tumor model in nude mice show that，compared withthe control group, the number of transfection shRNA-Ezrin-2on cell migration isless than transfection pEGFP C1/Ezrin. It show that Ezrin gene silencing can blockthe invasive growth of U251and U87, over expression can promote migration,increase its infiltration growth, so Ezrin participation in the invasive growth of U251and U87.
4. To study the effects of Ezrin on migration of U251and U87, invasive growthmechanism, rt-pcr and Western blot analysis of shRNA Ezrin-2and over expressionvector pEGFP C1/Ezrin transfection cells the expression of Rac1, Results show thatexpression level of pEGFP-C1/Ezrin transferred group Rac1is higher thanshRNA-Ezrin-2transferred group and the control group, and shRNA-Ezrin-2transfected group is lower than control group. The results indicate that Ezrin canactivate the Rac1, the effects of Ezrin on U251and U87cells are achieved throughRac1.
5. Transwell found the ability of U87cells migration is stronger than the U251cells, to know the reason of this difference, the structure of Ezrin was analyzed, andresults show that the Ezrin protein of U87cells in the66th,258,265and577-bit isvariable, and the C-terminus amino acid of34is the binding site of Ezrin and F-actin, N terminus43amino acids is the functional region，it is connected to the Cterminus107amino acids[26], we do not know in this area amino acid variations, whether affect the Ezrin and F-actin or combination of membranes and influence itsfunction, and then affects the cell migration. This study analysed Ezrin protein andfunction on the different infiltration ability of glioma cells with U251and U87throughbioinformatics methods. the U251cells Ezrin protein "matched" has362，and the U87cell Ezrin protein has1503，Ezrin structure function showed that,the number of PDBin Ezrin of U87is more than U251.According to the analysis, while the SCOP andCATH have the same hierarchical structure of the domain structure and hierarchicalclassification; Domain organization in Ezrin of U87cells had45, while the U251hadonly5. The further analysis of SWISS-MODEL, Coloring by residue error, the Ezrinof U87and U251cells had8difference, QMEAN4rate that the Ezrin of U87cellswas less than U251cells; SWISS-PDB Viewer showed that the258th,265th aminoacids was relatively in the inside of spatial structure. We speculated the function、domain and spatial structure of U87cells’ Ezrin was different from them of U251cells, resulting in the differences of U251and U87cells migration and invasioncapacity.
6. To test and verify the differences of the Ezrin protein’s structure which lead tothe differences of U251and U87cell migration and invasion ability, we used Ezrin ofU251cells to transfect U87cells, and then used Ezrin of U87cells to transfect U251cells, the results showed that U251cells of pEGFP-C1/Ezrin87migrate to the wound,the wound heal faster, while U87cells was transfected pEGFP-C1/Ezrin251whosenumber of migration was less than the pEGFP-C1/Ezrin87transfection group, and thewound healed slowly. The animal model of brain tumors in nude mice also confirmedthis result. The expression level of Rac1is also consistent with this result. It showedthat Ezrin can cause the differences of U251and U87cells migration and invasion,and achieve through activation of Rac1.
近年针对神经胶质瘤的分子靶标研制、开发了靶向治疗药物，临床试验有一定的治疗效果，但远未达到预期结果。此外，尽管科学工作者对肿瘤侵袭性生长的机制进行了大量研究，仍然不能深入了解脑胶质瘤浸润性生长的机制，因此深入研究其机制，寻找到其有效治疗的途径，是治疗神经胶质瘤、提高患者生存质量的关键。
肿瘤转移是恶性肿瘤的生物学特点，细胞运动能力增强导致其迁移和侵袭，细胞骨架的重塑是直接原因，而Ezrin是肌动蛋白与细胞膜及膜表面受体连接的桥梁，参与多种肌动蛋白的功能如细胞粘附，细胞运动和形态发生。在多种肿瘤组织表达上调，包括脑胶质瘤。但Ezrin在胶质瘤浸润性生长中的作用不清楚。
结合脑胶质瘤的生物学特性、治疗现状和Ezrin基因在肿瘤迁移和侵袭中的作用，本文研究了Ezrin与胶质瘤细胞U251和U87浸润性生长的相关性，并对其机制进行了探讨，主要研究结果：
1、成功构建Ezrin基因的shRNA表达载体，以脂质体Lipofectimine2000介导转染U87细胞，RT-PCR和Western blot检测结果表明，shRNA-Ezrin-2可沉默Ezrin表达，使其mRNA和蛋白表达量降低，确定为有效shRNA载体。
2、成功构建Ezrin基因表达载体pEGFP-C1/Ezrin。Western blot检测重组载体pEGFP-C1/Ezrin转染组Ezrin表达量高于空载体pEGFP-C1转染组和空白对照组。
3、shRNA-Ezrin-2与过表达载体pEGFP-C1/Ezrin分别转染U251和U87细胞，划痕试验结果显示Ezrin shRNA可阻断U251和U87细胞迁移，其过表达可促进细胞迁移。裸鼠脑瘤模型结果显示，与对照组对比，转染shRNA-Ezrin-2的细胞迁移数少，而转染pEGFP-C1/Ezrin的细胞迁移数相对较多，表明Ezrin基因沉默可阻断U251和U87细胞浸润性生长，过表达可促进迁移，增强其浸润生长，由此判断Ezrin参与U251和U87细胞浸润性生长。
4、为探讨Ezrin影响U251和U87细胞迁移、浸润性生长的机制，RT-PCR和Western blot分析shRNA-Ezrin-2与过表达载体pEGFP-C1/Ezrin转染细胞的Rac1的表达，结果显示，pEGFP-C1/Ezrin转染组Rac1表达量高于shRNA-Ezrin-2转染组和对照组，而shRNA-Ezrin-2转染组低于对照组。表明Ezrin可激活Rac1，Ezrin对U251和U87细胞的影响是通过Rac1实现的。
5、Transwell发现U87细胞的迁移能力强于U251细胞，为分析这种差异的原因，对Ezrin结构进行了分析，结果显示，U87细胞的Ezrin蛋白在第66、258、265和577位发生变异，而C端的34氨基酸是Ezrin与F-actin结合的位点，N端的296个氨基酸是与C端107个氨基酸残基相联系的功能域[22]，在此区域内发生氨基酸变异，是否影响Ezrin与F-actin或细胞膜的结合而影响其功能，从而影响细胞的迁移。本研究对具有不同浸润能力的脑胶质瘤细胞U251和U87的Ezrin蛋白功能和结构通过生物信息学方法加以分析、说明。Ezrin的蛋白功能分析显示，与U251细胞Ezrin“matched”的蛋白有362个，与U87细胞Ezrin“matched”的蛋白却有1503个；Ezrin的结构分析显示，U87细胞Ezrin的PDB多于U251细胞的，而SCOP和CATH所显示的结构域的结构分级和分层分级相同；U87细胞Ezrin的“Domain organisation”有45个，而U251细胞的Ezrin只有5个。SWISS-MODEL进一步分析，Coloring by residue error，U87细胞Ezrin有8处与U251细胞的不同，QMEAN4评分U87细胞Ezrin低于U251细胞的；SWISS-PDBViewer显示第258、265位氨基酸相对位于空间结构的内侧。推测U87细胞Ezrin的功能、结构域及空间结构均不同于U251细胞，导致了U251和U87细胞的迁移和浸润能力不同。
6、为验证Ezrin蛋白结构的差异造成U251和U87细胞迁移和浸润能力不同，本研究将U251细胞的Ezrin转染U87细胞，再将U87细胞的转染U251细胞，结果显示pEGFP-C1/Ezrin87转染的U251细胞大量迁移至伤口，伤口愈合较快，而转染pEGFP-C1/Ezrin251的U87细胞迁移的细胞数少于pEGFP-C1/Ezrin87转染组，伤口愈合较慢。裸鼠脑瘤动物模型也证实了这种结果。Rac1的表达量也与这种结果吻合。表明Ezrin可造成U251和U87细胞迁移、侵袭能力不同，且通过激活Rac1实现的。
Glioma is the tumor in the neural ectoderm, is the most common type of primaryintracranial tumors, it has high incidence and mortality, the rate of incidence is3~10per100thousand, accounted for46%of all intracranial tumors,1%~3%of systemicmalignant tumors,5-year survival rate is20%~30%[12]，and is a difficulty pointsfor the central nervous system diseases. Surgical resection and radiotherapy (RT),supplemented by chemotherapy is the current treatment standard, but gliomatreatment resistance, making very poor prognosis in glioma, average age12-15months[2-4]. Although in recent years, with the development and application of neuralimaging and intraoperative tumor tracer technology, it makes progress in the treatmentof glioma, but also difficult to ensure that predominantly surgical treatment cancompletely eradicate the tumor, the basic reason is the growth of gliomacharacteristics.
Recent years base on the research of gliomas molecular targets, targeted therapydrugs the development, clinical trial has certain therapeutic effect, but far fromexpected results. Moreover, although workers have done many studies on themechanism of invasive tumor growth, but still can't solve the mechanism of gliomainvasive growth, so further study of the mechanism and finding the effective way oftreatment, is the key to treatment of glioma and improve the quality of survival.
Tumor metastasis is the biological characteristics of malignant tumor, cellmovement ability enhanced lead to the migration and invasion, cytoskeletonremodeling is a direct reason, and Ezrin is actin bridge connected to the cellmembrane and membrane surface receptor[18], involved in many kinds of actinfunctions such as cell adhesion[20], cell movement and morphogenesis[21].Up-regulated the expression of variety of tumor tissue[8-15], including glioma. But therole of Ezrin in infiltrating growth of gliomas is not clear.
Combine with the current situation of biological characteristics, treatment ofglioma and the role of Ezrin genes in tumor migration and invasion, this paper studiesthe relationship of invasive growth between Ezrin and glioma cells U87、U251, and discuss the mechanism. The main research results:
1.The shRNA’s expression vector of Ezrin gene was constructed successfully,and U87cells were transfected by liposomes Lipofectimine2000, RT-PCR andWestern blot results showed that shRNA-Ezrin-2can be used to be silent theexpression of Ezrin, and made the expression levels of mRNA and protein decreased,it was identified to be valid shRNA vector.
2. The pEGFP-C1/Ezrin that was the expression vector of Ezrin gene wasconstructed successfully. Western blot detect the recombinant vector pEGFP-C1/Ezrinturn transfection group that Ezrin expression levels was higher than the empty vectorpEGFP-C1transfection group and blank control group.
3. After U87cells were transfected by shRNA vectors and expression vectors ofEzrin gene respectively, scratch experiments show that Ezrin shRNA can block themigration of U251and U87cells, and its over-expression can promote the cellmigration. The result of Brain tumor model in nude mice show that，compared withthe control group, the number of transfection shRNA-Ezrin-2on cell migration isless than transfection pEGFP C1/Ezrin. It show that Ezrin gene silencing can blockthe invasive growth of U251and U87, over expression can promote migration,increase its infiltration growth, so Ezrin participation in the invasive growth of U251and U87.
4. To study the effects of Ezrin on migration of U251and U87, invasive growthmechanism, rt-pcr and Western blot analysis of shRNA Ezrin-2and over expressionvector pEGFP C1/Ezrin transfection cells the expression of Rac1, Results show thatexpression level of pEGFP-C1/Ezrin transferred group Rac1is higher thanshRNA-Ezrin-2transferred group and the control group, and shRNA-Ezrin-2transfected group is lower than control group. The results indicate that Ezrin canactivate the Rac1, the effects of Ezrin on U251and U87cells are achieved throughRac1.
5. Transwell found the ability of U87cells migration is stronger than the U251cells, to know the reason of this difference, the structure of Ezrin was analyzed, andresults show that the Ezrin protein of U87cells in the66th,258,265and577-bit isvariable, and the C-terminus amino acid of34is the binding site of Ezrin and F-actin, N terminus43amino acids is the functional region，it is connected to the Cterminus107amino acids[26], we do not know in this area amino acid variations, whether affect the Ezrin and F-actin or combination of membranes and influence itsfunction, and then affects the cell migration. This study analysed Ezrin protein andfunction on the different infiltration ability of glioma cells with U251and U87throughbioinformatics methods. the U251cells Ezrin protein "matched" has362，and the U87cell Ezrin protein has1503，Ezrin structure function showed that,the number of PDBin Ezrin of U87is more than U251.According to the analysis, while the SCOP andCATH have the same hierarchical structure of the domain structure and hierarchicalclassification; Domain organization in Ezrin of U87cells had45, while the U251hadonly5. The further analysis of SWISS-MODEL, Coloring by residue error, the Ezrinof U87and U251cells had8difference, QMEAN4rate that the Ezrin of U87cellswas less than U251cells; SWISS-PDB Viewer showed that the258th,265th aminoacids was relatively in the inside of spatial structure. We speculated the function、domain and spatial structure of U87cells’ Ezrin was different from them of U251cells, resulting in the differences of U251and U87cells migration and invasioncapacity.
6. To test and verify the differences of the Ezrin protein’s structure which lead tothe differences of U251and U87cell migration and invasion ability, we used Ezrin ofU251cells to transfect U87cells, and then used Ezrin of U87cells to transfect U251cells, the results showed that U251cells of pEGFP-C1/Ezrin87migrate to the wound,the wound heal faster, while U87cells was transfected pEGFP-C1/Ezrin251whosenumber of migration was less than the pEGFP-C1/Ezrin87transfection group, and thewound healed slowly. The animal model of brain tumors in nude mice also confirmedthis result. The expression level of Rac1is also consistent with this result. It showedthat Ezrin can cause the differences of U251and U87cells migration and invasion,and achieve through activation of Rac1.
引文
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