MiR-218下调Slit2-Robo1通路抑制胶质瘤细胞增殖、侵袭和迁移的机制研究
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摘要
第一部分人脑胶质瘤中miR-218和Robo1的表达及意义
目的探讨人脑胶质瘤miR-218和Robo1的表达及意义。
方法应用实时荧光定量PCR(qRT-PCR)检测胶质瘤组织Ⅰ和Ⅱ级10例、Ⅲ、Ⅳ级胶质瘤组织各10例和行内减压的正常脑组织10例的miR-218表达，Western blot和免疫组织化学法检测Slit2和Robo1蛋白的表达水平，分析miR-218与Slit2-Robo1通路的相关性。
结果相对于正常脑组织，RT-PCR结果提示miR-218在Ⅰ、Ⅱ级胶质瘤组织中表达减少(P<0.05)，在Ⅲ、Ⅳ级胶质瘤组织中表达明显减少(P<0.01)；Slit2在正常脑神经元中显著表达，而在胶质瘤组织中表达水平降低，并且随着肿瘤恶性程度的增高，其表达依次降低。然而Robo1的表达与之相反，其不仅在正常脑神经元中有表达，在各级胶质瘤组织都表达增高。
结论胶质瘤组织中miR-218表达明显减少，Slit2在胶质瘤组织中表达同样减少，与miR-218表达呈正相关，Robo1在胶质瘤组织中表达异常增加，与miR-218表达呈负相关，三者的表达水平对评价胶质瘤良恶性程度有重要参考价值。
第二部分miR-218通过下调Slit2-Robo1通路抑制U251的细胞增殖、侵袭和迁移
目的研究上调人脑胶质瘤系U251中miR-218的表达对Slit2-Robo1通路的影响及可能的机制。
方法将miR-218的类似物mimics(miR-218mimics)或NC的类似物mimics(mimics NC)瞬时转染U251细胞，设一组不做任何转染的空白对照，qRT-PCR和Western blot分别检测miR-218的预测靶基因Slit2-mRNA、Robo1–mRNA和蛋白表达水平。应用MTT法检测细胞生长情况,流式细胞仪检测细胞周期分布变化,动物实验评价体内条件下肿瘤生长能力变化，应用Transwell小室体外侵袭和迁徙实验检测转染后细胞的体外侵袭和迁移能力改变。应用双荧光素酶分析方法鉴定miR-218和Robo13＇UTR的表达调节关系。
结果U251细胞中转染miR-218mimics成功后miR-218表达增加；Slit2在胶质瘤细胞中同样表达增加，而Robo1表达显著下降。miR-218显著减弱U251增殖能力，流式细胞周期检测提示U251出现了G0/G1期阻滞，动物实验反应体内条件下肿瘤生长能力显著减弱。Transwell实验提示miR-218抑制U251胶质瘤细胞的体外侵袭及迁移能力。双荧光素酶报告基因实验提示miR-218通过直接与Robo1mRNA3＇UTR结合负调节其表达。
结论miR-218表达可下调Slit2-Robo1通路抑制U251细胞增殖、侵袭及迁移能力；miR-218的生物效应可能与调节潜在靶基因Robo1有关。
第三部分miR-218通过调节Robo1基因抑制U251细胞增殖、侵袭和迁移
目的探讨miR-218通过调节Robo1基因抑制U251细胞增殖、侵袭和转移的作用机制。
方法用siRobo1下调Robo1在U251中的表达，实验分四组①空白对照组；②miR-218mimics组；③Robo1siCont组；④Robo1siRNA组。Western blot分别检测miR-218的预测靶基因Robo1蛋白表达水平。应用MTT法检测细胞生长情况,流式细胞仪检测细胞周期分布变化,应用Transwell小室体外侵袭和迁徙实验检测转染后细胞的体外侵袭和迁移能力改变。
结果与空白对照组和Robo1siCont组比较miR-218mimics和Robo1siRNA组Robo1蛋白表达水平显著下降（P＜0.01），Robo1siRNA组与miR-218mimics组Robo1蛋白表达水平相当，无显著差异（P＞0.05）。MTT结果提示Robo1siRNA组和miR-218mimics组U251增殖能力显著减弱，流式细胞周期检测提示Robo1siRNA组和miR-218mimics组U251出现了G0/G1期阻滞。Transwell实验提示Robo1siRNA组和miR-218mimics组显著抑制U251体外侵袭及迁移。下调Robo1的表达引起的U251细胞增殖抑制、细胞周期G0/G1期阻滞和体外侵袭及迁移效应与上调miR-218在U251细胞的表达引起的效应类似，且效果相当。
结论miR-218通过对其下游靶基因Robo1的负性调控抑制U251细胞增殖、体外侵袭及迁移。
Part I The expression and meaning of miR-218and Robo1in humanglioma tissue
Objective：To explore the expression and meaning of miR-218and Robo1in humanglioma tissue.
Method:The expression levels of miR-218in40cases of different grades of gliomastissues and10control brain tissues were detected by means of qRT-PCR.The expressionlevels of Slit2and Robo1were evaluated using Western blot and immunocytochemistry.Whilst the relationships between miR-218and Slit2-Robo1pathway were analyzed.
Results:Quantitive real-time RT-PCR analysis revealed that miR-218exression werereduced in Ⅰ, Ⅱ-grade glioma tissues(P<0.05)and markedly reduced in Ⅲ, Ⅳ-gradeglioma tissues(P<0.01) versus normal brain tissuees,that Slit2is distinctly expressed bynormal cerebral neurons,but at very low levels in all-grade glioma tissues, moreover,withthe progression of malignant glioma,the expression of Slit2is gradually decreased or evensilenced.However,Robo1is not only expressed in normal brain neurons,but alsoover-expressed in different grades of gliomas(P<0.05).
Conclusion:MiR-218exression were markedly reduced in all-grade glioma tissues,meanwhile the expression of Slit2in all-grade glioma tissues were decreased;there was apositive correlation between the expression of Slit2and miR-218; the expression of Robo1in all-grade glioma tissues were markedly increased, there was a negative correla tionbetween the expression of Robo1and miR-218.
PartⅡ MiR-218inhibits glioma cells proliferation、high invasiveenessand migratory through downregulation the Slit2-Robo1pathway
Objective：To explore the effect on Slit2-Robo1pathway through miR-218over-expression in human U251glioma cells
Method:Human U251glioma cells were transfected with miR-218mimics and mimics NC,the expression levels of mRNA and protein expression of Robo1and Slit2aftermiR-218transfection were detected by qRT-PCR and westemb1otting analysis.Thechanges of cell growth and proliferation were determined by MTT method and the changesof cell were determined by cycle flow cytometry assay.The migration and invasion ofglioma cells were detected by Transwell assay.The change of tumor growth in vivo wasevaluated by animal experiment. A computational search revealed a conserved target site ofmiR-218within the3＇-untranslated region of Robo1.Luciferase reporter assay wasperformed to examine the effects of miR-218on expression of potential target geneRobo1.
Results:MiR-218was up-regulated after the U251cells transfection with miR-218mimics.over-expression of miR-218decreased mRNA and protein levels of Robo1,andincreased mRNA and protein levels of Slit2.The proliferation was significantly decreasedby the MTT assay and the cell cycle was arrested in G0/G1phase by flow cytometry assayafter transfection with miR-218mimics. Nude mouse tumorigenicity assay suggested thatmiR-218may play a crucial role in the proliferation of glioma cells in vitro. Transwellassay demonstrated that the migration and invasion capability of tumor cells decreasedafter transfection with miR-218mimics.Luciferase reporter assay suggested that miR-218might inhibit Robo1expression through interaction between miR-218and3′UTR ofRobo1.
Conclusion: MiR-218may inhibit glioma cells proliferation、high invasiveness andmigratory through downregulation the Slit2-Robo1pathway;and the biological effect ofmiR-218in glioma cells is probably have relation to regulating its potential target geneRobo1.
PartⅢ MiR-218inhibits glioma cell proliferation、high invasiveeness andmigratory through negatively regulating the expression of Robo1gene
Objective：To explore the mechanism on miR-218inhibits glioma cells proliferation、high invasiveeness and migratory through negatively regulating the expression of Robo1gene.
Method:Downregulating the expression of Robo1in U251cells by siRobo1,the expe riment were divided into:①control group;②m iR-218mimics group;③Robo1siContgroup;④Robo1siRNA group.The expression levels of protein expression of Robo1aftertransfection were detected by westemb1otting analysis.The changes of cell growth andproliferation were determined by MTT method and the changes of cell cycle weredetermined by cycle flow cytometry assay.The migration and invasion of glioma cells weredetected by Transwell assay.
Results:Westemb1otting analysis revealed that Robo1exression were markedlyreduced in miR-218mimics group and Robo1siRNA group versus control group andRobo1siCont group（P＜0.01）.The Robo1exression levels in Robo1siRNA group wereequal to in miR-218mimics group（P＞0.05）.MTT assays showed that downregulation ofRobo1significantly inhibited the proliferation of U251cells and the cell cycle was arrestedin G0/G1phase by flow cytometry assay compared with control group.Furthermore,transwell assay demonstrated that the migration and invasion capability of tumor cellsdecreased after transfection with Robo1siRNA. Importantly,downregulation of Robo1inU251cells could inhibit proliferation and block G0/G1transition,which was consistentwith the effect of miR-218overexpression in U251cells.
Conclusion:MiR-218inhibits glioma cells proliferation、high invasiveeness andmigratory through negatively regulating the expression of Robo1gene.
目的探讨人脑胶质瘤miR-218和Robo1的表达及意义。
方法应用实时荧光定量PCR(qRT-PCR)检测胶质瘤组织Ⅰ和Ⅱ级10例、Ⅲ、Ⅳ级胶质瘤组织各10例和行内减压的正常脑组织10例的miR-218表达，Western blot和免疫组织化学法检测Slit2和Robo1蛋白的表达水平，分析miR-218与Slit2-Robo1通路的相关性。
结果相对于正常脑组织，RT-PCR结果提示miR-218在Ⅰ、Ⅱ级胶质瘤组织中表达减少(P<0.05)，在Ⅲ、Ⅳ级胶质瘤组织中表达明显减少(P<0.01)；Slit2在正常脑神经元中显著表达，而在胶质瘤组织中表达水平降低，并且随着肿瘤恶性程度的增高，其表达依次降低。然而Robo1的表达与之相反，其不仅在正常脑神经元中有表达，在各级胶质瘤组织都表达增高。
结论胶质瘤组织中miR-218表达明显减少，Slit2在胶质瘤组织中表达同样减少，与miR-218表达呈正相关，Robo1在胶质瘤组织中表达异常增加，与miR-218表达呈负相关，三者的表达水平对评价胶质瘤良恶性程度有重要参考价值。
第二部分miR-218通过下调Slit2-Robo1通路抑制U251的细胞增殖、侵袭和迁移
目的研究上调人脑胶质瘤系U251中miR-218的表达对Slit2-Robo1通路的影响及可能的机制。
方法将miR-218的类似物mimics(miR-218mimics)或NC的类似物mimics(mimics NC)瞬时转染U251细胞，设一组不做任何转染的空白对照，qRT-PCR和Western blot分别检测miR-218的预测靶基因Slit2-mRNA、Robo1–mRNA和蛋白表达水平。应用MTT法检测细胞生长情况,流式细胞仪检测细胞周期分布变化,动物实验评价体内条件下肿瘤生长能力变化，应用Transwell小室体外侵袭和迁徙实验检测转染后细胞的体外侵袭和迁移能力改变。应用双荧光素酶分析方法鉴定miR-218和Robo13＇UTR的表达调节关系。
结果U251细胞中转染miR-218mimics成功后miR-218表达增加；Slit2在胶质瘤细胞中同样表达增加，而Robo1表达显著下降。miR-218显著减弱U251增殖能力，流式细胞周期检测提示U251出现了G0/G1期阻滞，动物实验反应体内条件下肿瘤生长能力显著减弱。Transwell实验提示miR-218抑制U251胶质瘤细胞的体外侵袭及迁移能力。双荧光素酶报告基因实验提示miR-218通过直接与Robo1mRNA3＇UTR结合负调节其表达。
结论miR-218表达可下调Slit2-Robo1通路抑制U251细胞增殖、侵袭及迁移能力；miR-218的生物效应可能与调节潜在靶基因Robo1有关。
第三部分miR-218通过调节Robo1基因抑制U251细胞增殖、侵袭和迁移
目的探讨miR-218通过调节Robo1基因抑制U251细胞增殖、侵袭和转移的作用机制。
方法用siRobo1下调Robo1在U251中的表达，实验分四组①空白对照组；②miR-218mimics组；③Robo1siCont组；④Robo1siRNA组。Western blot分别检测miR-218的预测靶基因Robo1蛋白表达水平。应用MTT法检测细胞生长情况,流式细胞仪检测细胞周期分布变化,应用Transwell小室体外侵袭和迁徙实验检测转染后细胞的体外侵袭和迁移能力改变。
结果与空白对照组和Robo1siCont组比较miR-218mimics和Robo1siRNA组Robo1蛋白表达水平显著下降（P＜0.01），Robo1siRNA组与miR-218mimics组Robo1蛋白表达水平相当，无显著差异（P＞0.05）。MTT结果提示Robo1siRNA组和miR-218mimics组U251增殖能力显著减弱，流式细胞周期检测提示Robo1siRNA组和miR-218mimics组U251出现了G0/G1期阻滞。Transwell实验提示Robo1siRNA组和miR-218mimics组显著抑制U251体外侵袭及迁移。下调Robo1的表达引起的U251细胞增殖抑制、细胞周期G0/G1期阻滞和体外侵袭及迁移效应与上调miR-218在U251细胞的表达引起的效应类似，且效果相当。
结论miR-218通过对其下游靶基因Robo1的负性调控抑制U251细胞增殖、体外侵袭及迁移。
Part I The expression and meaning of miR-218and Robo1in humanglioma tissue
Objective：To explore the expression and meaning of miR-218and Robo1in humanglioma tissue.
Method:The expression levels of miR-218in40cases of different grades of gliomastissues and10control brain tissues were detected by means of qRT-PCR.The expressionlevels of Slit2and Robo1were evaluated using Western blot and immunocytochemistry.Whilst the relationships between miR-218and Slit2-Robo1pathway were analyzed.
Results:Quantitive real-time RT-PCR analysis revealed that miR-218exression werereduced in Ⅰ, Ⅱ-grade glioma tissues(P<0.05)and markedly reduced in Ⅲ, Ⅳ-gradeglioma tissues(P<0.01) versus normal brain tissuees,that Slit2is distinctly expressed bynormal cerebral neurons,but at very low levels in all-grade glioma tissues, moreover,withthe progression of malignant glioma,the expression of Slit2is gradually decreased or evensilenced.However,Robo1is not only expressed in normal brain neurons,but alsoover-expressed in different grades of gliomas(P<0.05).
Conclusion:MiR-218exression were markedly reduced in all-grade glioma tissues,meanwhile the expression of Slit2in all-grade glioma tissues were decreased;there was apositive correlation between the expression of Slit2and miR-218; the expression of Robo1in all-grade glioma tissues were markedly increased, there was a negative correla tionbetween the expression of Robo1and miR-218.
PartⅡ MiR-218inhibits glioma cells proliferation、high invasiveenessand migratory through downregulation the Slit2-Robo1pathway
Objective：To explore the effect on Slit2-Robo1pathway through miR-218over-expression in human U251glioma cells
Method:Human U251glioma cells were transfected with miR-218mimics and mimics NC,the expression levels of mRNA and protein expression of Robo1and Slit2aftermiR-218transfection were detected by qRT-PCR and westemb1otting analysis.Thechanges of cell growth and proliferation were determined by MTT method and the changesof cell were determined by cycle flow cytometry assay.The migration and invasion ofglioma cells were detected by Transwell assay.The change of tumor growth in vivo wasevaluated by animal experiment. A computational search revealed a conserved target site ofmiR-218within the3＇-untranslated region of Robo1.Luciferase reporter assay wasperformed to examine the effects of miR-218on expression of potential target geneRobo1.
Results:MiR-218was up-regulated after the U251cells transfection with miR-218mimics.over-expression of miR-218decreased mRNA and protein levels of Robo1,andincreased mRNA and protein levels of Slit2.The proliferation was significantly decreasedby the MTT assay and the cell cycle was arrested in G0/G1phase by flow cytometry assayafter transfection with miR-218mimics. Nude mouse tumorigenicity assay suggested thatmiR-218may play a crucial role in the proliferation of glioma cells in vitro. Transwellassay demonstrated that the migration and invasion capability of tumor cells decreasedafter transfection with miR-218mimics.Luciferase reporter assay suggested that miR-218might inhibit Robo1expression through interaction between miR-218and3′UTR ofRobo1.
Conclusion: MiR-218may inhibit glioma cells proliferation、high invasiveness andmigratory through downregulation the Slit2-Robo1pathway;and the biological effect ofmiR-218in glioma cells is probably have relation to regulating its potential target geneRobo1.
PartⅢ MiR-218inhibits glioma cell proliferation、high invasiveeness andmigratory through negatively regulating the expression of Robo1gene
Objective：To explore the mechanism on miR-218inhibits glioma cells proliferation、high invasiveeness and migratory through negatively regulating the expression of Robo1gene.
Method:Downregulating the expression of Robo1in U251cells by siRobo1,the expe riment were divided into:①control group;②m iR-218mimics group;③Robo1siContgroup;④Robo1siRNA group.The expression levels of protein expression of Robo1aftertransfection were detected by westemb1otting analysis.The changes of cell growth andproliferation were determined by MTT method and the changes of cell cycle weredetermined by cycle flow cytometry assay.The migration and invasion of glioma cells weredetected by Transwell assay.
Results:Westemb1otting analysis revealed that Robo1exression were markedlyreduced in miR-218mimics group and Robo1siRNA group versus control group andRobo1siCont group（P＜0.01）.The Robo1exression levels in Robo1siRNA group wereequal to in miR-218mimics group（P＞0.05）.MTT assays showed that downregulation ofRobo1significantly inhibited the proliferation of U251cells and the cell cycle was arrestedin G0/G1phase by flow cytometry assay compared with control group.Furthermore,transwell assay demonstrated that the migration and invasion capability of tumor cellsdecreased after transfection with Robo1siRNA. Importantly,downregulation of Robo1inU251cells could inhibit proliferation and block G0/G1transition,which was consistentwith the effect of miR-218overexpression in U251cells.
Conclusion:MiR-218inhibits glioma cells proliferation、high invasiveeness andmigratory through negatively regulating the expression of Robo1gene.
引文
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