益气解毒方对鼻咽癌细胞骨架结构及相关蛋白表达活性的干预效应研究
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摘要
目的：
观察益气解毒方对鼻咽癌细胞骨架结构及相关蛋白系统表达活性的影响,探讨其对鼻咽癌细胞转移潜能相关生物力学特性干预效应及其影响细胞迁徙运动潜能的可能作用机制,为寻找干预鼻咽癌细胞转移的新靶点提供实验依据。
方法：
32只BALB/c裸小鼠,随机分为模型组、益气解毒方治疗组、益气解毒方预防组和甲氨蝶呤阳性对照组,分别按照给药方案用药,取人鼻咽癌细胞株CNE2对数分裂期细胞,分别于各组动物右侧前腋皮下接种,以制备移植瘤模型,动态观察各组裸鼠移植瘤生长情况,测量移植瘤长短径,绘制移植瘤生长曲线；观察期满后处死动物,取瘤体称重,分别计算抑瘤率,切取标本分别制备石蜡包埋块及电镜标本。部分瘤体石蜡包埋块连续切片,常规苏木精-伊红染色后光学显微镜下观察病理组织学变化。部分瘤体透射电镜观察各组标本细胞骨架结构系统微管、微丝与中间丝等的形态变化,比较各组的差异。
免疫组化SABC法检测各组标本Cdc42、β-tubulin、F-actin、Ezrin表达活性,比较其组间差异。
结果：
各用药组裸鼠移植瘤体积与模型组相比较相对较小,差异均具有统计学意义(P<0.05)；3组的裸鼠抑瘤率分别为益气解毒方预防组58.35%、益气解毒汤治疗组30.03%、阳性对照组52.94%。
移植瘤组织的光镜观察显示,模型组瘤细胞排列密集甚至重叠,结构尚清晰。用药各组瘤细胞固缩,密度增加,轮廓变形,出现不同程度的凋亡。其中预防组可见凋亡小体。电镜显示各用药组瘤细胞较模型组细丝状骨架纤维有不同程度破坏,其中益气解毒方预防组瘤细胞胞质骨架稀疏,骨架纤维短且细碎,排列无极向,少见应力纤维束。
裸鼠移植瘤细胞骨架相关蛋白免疫组化SABC法检测显示,模型组与各用药组比较,其Cdc42、β-tubulin、F-actin、Ezrin表达活性较高,差异具有统计学意义(P<0.01),各组组间比较益气解毒方治疗组与阳性对照组差异无统计学意义(P>0.05),其余各组差异均有统计学意义(P<0.01)。
结论：
益气解毒方可通过抑制Cdc42蛋白的表达,诱导下调CNE2细胞Ezrin蛋白、骨架微丝蛋白F-actin及微管蛋白β-tubulin表达活性,破坏瘤细胞内的纤维状骨架,抑制而发挥其迁徙运动潜能的效应。
Objective:
To investigate the intervening effect of Qi-Boosting Toxin-Resolving Formula (QBTRF) on the structures of cystoskeleton and the expressive activities of associated protein system in the cells of nasopharyngeal carcinoma (NPC) to explore the possible affect of such an effect on the biodynamic mechanism underlying their metastatic potentiality of NPC to provide experimental evidences to identify new targets for intervening the potential metastatic process of the tumor.
Methods:
Thirty two BALB/c nude mice were randomly divided into 4 groups at first, i.e.modeling group (MG),preventing group (PG) with QBTRF, treating group (TG) with QBTRF and positive controlling group (PCG) treated by methotrexate,and treated with various treating procedures. Implanted tumors were established by injecting CNE2 cells subcutaneously into the anterior part of right axil of each group of animals.Then, they were sacrificed to separate tumor samples in the same way as above for measuring the same set of parameters,drawing the curves from the weight of the nude mice, the curve from growth of the tumors and weight of the tumors,evaluating the inhibiting rate of tumor growing. To take samples from the dissected tumors for histopathological observation on the cellular adhesive structure, by light microscopy and electron microscopy respectively.As a result of this,a comparative analysis could be made on the changeable ultra-structural differences among various groups to explore the possible biodynamics-relating morphology.
For an exploration on the biodynamic mechanism underlying the metastatic process of tumor cells, immunohistochemical ABC procedures were taken to determine the expressive activities of protein system in the terms of biodynamic correlation, such as Cdc42,β-tubulin, F-actin and Ezrin, among different groups with a comparative analysis on these indexes as determined on the paraffin embedded tissue samples.
Results:
As measured on the volumes of implanted tumors after treatment with a comparative analysis with that of MG, there were statistically significant differences in the volumes of tumors among the nude mice of PG, TG and PCG (P<0.05),with the inhibitory rates of tumor growing being 58.35%,30.03% and 52.94% for them respectively.
For light microscopy, the tissue samples were embedded in paraffin to make series of sections respectively, stained by conventional methods of hematoxylin-eosin procedure, for comparative observation on the histopathological changes among different groups.Electron microscopy shows the medication group tumor cells a model group of filamentous skeleton fiber have some form of destruction, supplementing party prevention group of cytoskeleton sparse, skeleton fiber short and to the chronology, arrange for endless,rare stress fiber bundles.The samples for transmission electron microscopy were showed that the formation of fibrous skeletons were distroyed in an inhibited way in varying degrees.
As determined by SABC immunohistochemistry followed by image analysis on the cellular adhesion-relating proteins in sections of various groups,the expressive activities of Cdc42,β-tubulin, F-actin and Ezrin were much higher in the samples of MG than that of PG, TG and PCG, with significantly statistical differences among them (P<0.01).
Conclusions:
It can be concluded from this experimental study that QBTRF bring about inhibitory effect on the metastatic potentiality of NPC cells via the mechanisms of expression inhibition of Cdc42 to induce decreased expressive activity of cytoskeletal filament protein F-actin and protein Ezrin microtubule proteinβ-tubulin in these cells so as to distroy the formation of fibrous skeletons in an inhibited way and bring about through its intervening effect on their biodynamic mechanism.
观察益气解毒方对鼻咽癌细胞骨架结构及相关蛋白系统表达活性的影响,探讨其对鼻咽癌细胞转移潜能相关生物力学特性干预效应及其影响细胞迁徙运动潜能的可能作用机制,为寻找干预鼻咽癌细胞转移的新靶点提供实验依据。
方法：
32只BALB/c裸小鼠,随机分为模型组、益气解毒方治疗组、益气解毒方预防组和甲氨蝶呤阳性对照组,分别按照给药方案用药,取人鼻咽癌细胞株CNE2对数分裂期细胞,分别于各组动物右侧前腋皮下接种,以制备移植瘤模型,动态观察各组裸鼠移植瘤生长情况,测量移植瘤长短径,绘制移植瘤生长曲线；观察期满后处死动物,取瘤体称重,分别计算抑瘤率,切取标本分别制备石蜡包埋块及电镜标本。部分瘤体石蜡包埋块连续切片,常规苏木精-伊红染色后光学显微镜下观察病理组织学变化。部分瘤体透射电镜观察各组标本细胞骨架结构系统微管、微丝与中间丝等的形态变化,比较各组的差异。
免疫组化SABC法检测各组标本Cdc42、β-tubulin、F-actin、Ezrin表达活性,比较其组间差异。
结果：
各用药组裸鼠移植瘤体积与模型组相比较相对较小,差异均具有统计学意义(P<0.05)；3组的裸鼠抑瘤率分别为益气解毒方预防组58.35%、益气解毒汤治疗组30.03%、阳性对照组52.94%。
移植瘤组织的光镜观察显示,模型组瘤细胞排列密集甚至重叠,结构尚清晰。用药各组瘤细胞固缩,密度增加,轮廓变形,出现不同程度的凋亡。其中预防组可见凋亡小体。电镜显示各用药组瘤细胞较模型组细丝状骨架纤维有不同程度破坏,其中益气解毒方预防组瘤细胞胞质骨架稀疏,骨架纤维短且细碎,排列无极向,少见应力纤维束。
裸鼠移植瘤细胞骨架相关蛋白免疫组化SABC法检测显示,模型组与各用药组比较,其Cdc42、β-tubulin、F-actin、Ezrin表达活性较高,差异具有统计学意义(P<0.01),各组组间比较益气解毒方治疗组与阳性对照组差异无统计学意义(P>0.05),其余各组差异均有统计学意义(P<0.01)。
结论：
益气解毒方可通过抑制Cdc42蛋白的表达,诱导下调CNE2细胞Ezrin蛋白、骨架微丝蛋白F-actin及微管蛋白β-tubulin表达活性,破坏瘤细胞内的纤维状骨架,抑制而发挥其迁徙运动潜能的效应。
Objective:
To investigate the intervening effect of Qi-Boosting Toxin-Resolving Formula (QBTRF) on the structures of cystoskeleton and the expressive activities of associated protein system in the cells of nasopharyngeal carcinoma (NPC) to explore the possible affect of such an effect on the biodynamic mechanism underlying their metastatic potentiality of NPC to provide experimental evidences to identify new targets for intervening the potential metastatic process of the tumor.
Methods:
Thirty two BALB/c nude mice were randomly divided into 4 groups at first, i.e.modeling group (MG),preventing group (PG) with QBTRF, treating group (TG) with QBTRF and positive controlling group (PCG) treated by methotrexate,and treated with various treating procedures. Implanted tumors were established by injecting CNE2 cells subcutaneously into the anterior part of right axil of each group of animals.Then, they were sacrificed to separate tumor samples in the same way as above for measuring the same set of parameters,drawing the curves from the weight of the nude mice, the curve from growth of the tumors and weight of the tumors,evaluating the inhibiting rate of tumor growing. To take samples from the dissected tumors for histopathological observation on the cellular adhesive structure, by light microscopy and electron microscopy respectively.As a result of this,a comparative analysis could be made on the changeable ultra-structural differences among various groups to explore the possible biodynamics-relating morphology.
For an exploration on the biodynamic mechanism underlying the metastatic process of tumor cells, immunohistochemical ABC procedures were taken to determine the expressive activities of protein system in the terms of biodynamic correlation, such as Cdc42,β-tubulin, F-actin and Ezrin, among different groups with a comparative analysis on these indexes as determined on the paraffin embedded tissue samples.
Results:
As measured on the volumes of implanted tumors after treatment with a comparative analysis with that of MG, there were statistically significant differences in the volumes of tumors among the nude mice of PG, TG and PCG (P<0.05),with the inhibitory rates of tumor growing being 58.35%,30.03% and 52.94% for them respectively.
For light microscopy, the tissue samples were embedded in paraffin to make series of sections respectively, stained by conventional methods of hematoxylin-eosin procedure, for comparative observation on the histopathological changes among different groups.Electron microscopy shows the medication group tumor cells a model group of filamentous skeleton fiber have some form of destruction, supplementing party prevention group of cytoskeleton sparse, skeleton fiber short and to the chronology, arrange for endless,rare stress fiber bundles.The samples for transmission electron microscopy were showed that the formation of fibrous skeletons were distroyed in an inhibited way in varying degrees.
As determined by SABC immunohistochemistry followed by image analysis on the cellular adhesion-relating proteins in sections of various groups,the expressive activities of Cdc42,β-tubulin, F-actin and Ezrin were much higher in the samples of MG than that of PG, TG and PCG, with significantly statistical differences among them (P<0.01).
Conclusions:
It can be concluded from this experimental study that QBTRF bring about inhibitory effect on the metastatic potentiality of NPC cells via the mechanisms of expression inhibition of Cdc42 to induce decreased expressive activity of cytoskeletal filament protein F-actin and protein Ezrin microtubule proteinβ-tubulin in these cells so as to distroy the formation of fibrous skeletons in an inhibited way and bring about through its intervening effect on their biodynamic mechanism.
引文
(1)闵华庆主编.鼻咽癌.第一版,中国医药科技出版社,北京.2003：313.
(2)M a B B,Chan A T. Systemic treatm ent strategies and therapeutic monitoring for advanced nasopharyngeal carcinoma[J].Expert Rev Anticancer Ther,2006,6(3): 383-394.
(3)Hall A. Rho GTPases and the actin cytoskeleton[J].Science,1998,279(5350): 509-514.
(5)Sahai E,Marshall C1.RHO-GTPases and cancer[J].Nat Re'o Cancer,2002, 2(2):133-142.
(6)Sah VP,SeasholtzTM,Sagil SA, et al.He role of Rho in G protein couple receptr signal transduction[J].Annu Rev Pharmacol Toxicol,2000,40:459-489
(7)Mackay DJG, Hall A.Rho GTPases[J].J Biol Chem,1998,273(33); 20685-20688
(8)Nobes CD,Hall A. Rho GT Pases control polarity,protrusion,and ad hesion duing cell movement [J].J Cell Biol,1999,144:1235-1244.
(9)Meriane M, Marc S,Communale F, et al.Cdc42Hs and Racl GTPases induce the collapse of the vimentin intermediate filament network [J].J Biol Chem,2000,275(42):33046-3 3052.
(10)Downward J.Targeting Ras signaling pathways in cancer thetapy[J].Nat Rev Cancer,2003,3(1):11-22.
(11)田道法,唐发清,陈协云,等.益气解毒颗粒对鼻咽癌高危人群EB病毒感染活性的抑制作用的临床观察[J].湖南中医学院学报,2003,20(3)：47-49.
(12)唐发清,田道法.黄连及复方对鼻咽癌细胞裸鼠移植瘤的抑制作用[J].癌症,1995,(14)：459-460.
(13)唐发清,田道法,陈朝晖,等.益气解毒颗粒对大鼠鼻咽癌变中端粒酶和端粒酶RNA表达的影响[J].湖南医科大学学报,2001,26(4)：301-304.
(14)何迎春,等.中药益气解毒颗粒下调端粒酶活性抑制鼻咽癌细胞的生长[J].中 国现代医学杂志,2005,15(1)：53-55.
(15)陈朝晖,等.益气解毒颗粒对大鼠鼻咽癌变中端粒酶和端粒酶RNA表达的影响[J].湖南中医学院学报,2001,26(4)：301-304.
(16)唐发清,等.益气解毒颗粒对二亚硝基哌嗪诱导人胚鼻咽上皮细胞转化的阻抑作用[J].湖南医科大学学报,2001,21(3)：18-20.
(17)唐发清,等.益气解毒片对鼻咽癌细胞端粒酶和端粒酶RNA抑制作用的实验研究[J].湖南医科大学学报,2000,20(1)：15-17.
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(20)唐发清,等.中药益气解毒颗粒对鼻咽癌裸鼠移植瘤蛋白质表达的影响[J].中南大学学报：医学版,2004,29(5)：577-582.
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(2)M a B B,Chan A T. Systemic treatm ent strategies and therapeutic monitoring for advanced nasopharyngeal carcinoma[J].Expert Rev Anticancer Ther,2006,6(3): 383-394.
(3)Hall A. Rho GTPases and the actin cytoskeleton[J].Science,1998,279(5350): 509-514.
(5)Sahai E,Marshall C1.RHO-GTPases and cancer[J].Nat Re'o Cancer,2002, 2(2):133-142.
(6)Sah VP,SeasholtzTM,Sagil SA, et al.He role of Rho in G protein couple receptr signal transduction[J].Annu Rev Pharmacol Toxicol,2000,40:459-489
(7)Mackay DJG, Hall A.Rho GTPases[J].J Biol Chem,1998,273(33); 20685-20688
(8)Nobes CD,Hall A. Rho GT Pases control polarity,protrusion,and ad hesion duing cell movement [J].J Cell Biol,1999,144:1235-1244.
(9)Meriane M, Marc S,Communale F, et al.Cdc42Hs and Racl GTPases induce the collapse of the vimentin intermediate filament network [J].J Biol Chem,2000,275(42):33046-3 3052.
(10)Downward J.Targeting Ras signaling pathways in cancer thetapy[J].Nat Rev Cancer,2003,3(1):11-22.
(11)田道法,唐发清,陈协云,等.益气解毒颗粒对鼻咽癌高危人群EB病毒感染活性的抑制作用的临床观察[J].湖南中医学院学报,2003,20(3)：47-49.
(12)唐发清,田道法.黄连及复方对鼻咽癌细胞裸鼠移植瘤的抑制作用[J].癌症,1995,(14)：459-460.
(13)唐发清,田道法,陈朝晖,等.益气解毒颗粒对大鼠鼻咽癌变中端粒酶和端粒酶RNA表达的影响[J].湖南医科大学学报,2001,26(4)：301-304.
(14)何迎春,等.中药益气解毒颗粒下调端粒酶活性抑制鼻咽癌细胞的生长[J].中 国现代医学杂志,2005,15(1)：53-55.
(15)陈朝晖,等.益气解毒颗粒对大鼠鼻咽癌变中端粒酶和端粒酶RNA表达的影响[J].湖南中医学院学报,2001,26(4)：301-304.
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