沉默VEGF-C基因后膀胱癌T24细胞的蛋白质组学及maspin蛋白的表达和功能研究
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摘要
第一部分沉默VEGF-C基因后膀胱癌T24细胞的蛋白质组学研究
目的寻找在膀胱癌T24细胞中与VEGF-C基因功能相关的蛋白,为了解VEGF-C基因在膀胱癌的作用机制提供新的思路。
方法采用RNA干扰技术沉默人膀胱癌T24细胞中的VEGF-C基因,再抽提沉默组和对照组的肿瘤细胞全蛋白,利用荧光差异显示双向凝胶电泳技术获取蛋白质电泳图谱。通过对差异表达的蛋白质点定量和鉴定,筛选出与VEGF-C基因可能有相互作用的蛋白质。
结果沉默组和对照组细胞之间存在25个差异蛋白质点。经质谱鉴定后,23个蛋白质点被成功鉴定。这些蛋白质包括：细胞骨架蛋白、信号转导蛋白、分子伴侣、细胞增殖和转移相关蛋白、生物合成蛋白、能量代谢蛋白等。在这23个蛋白质中,10个蛋白质在沉默组中表达上调,另外13个蛋白质沉默组中表达下调。
结论联合应用RNA干扰技术和比较蛋白质组学方法,高通量筛选膀胱癌细胞中VEGF-C功能相关蛋白具有可行性。本研究发现了23个潜在的与VEGF-C功能相关的蛋白质,为进一步阐明VEGF-C促膀胱癌恶性发展的作用机制提供了新的线索和思路。
第二部分maspin对膀胱癌T24细胞生物学行为的影响和机制研究
目的研究maspin对膀胱癌T24细胞生物学行为的影响,并初步探讨其可能机制。
方法首先通过甲基化特异性PCR法检测naspin启动子在膀胱癌T24细胞中的甲基化状态,再利用Real Time PCR和Western blotting方法观察不同浓度的5-氮杂-2’-脱氧胞苷(5-aza-2'-deoxycytidine,5-Aza-CdR,0,0.25,0.5,1,2μmol/L)对naspin的mRNA和蛋白表达水平的影响。通过MTT实验观察maspin对T24细胞的增殖能力的影响,通过流式细胞仪观察maspin对T24细胞的凋亡的影响,通过迁移和侵袭实验观察maspin对T24细胞的迁移和侵袭能力的影响,并通过Western blotting方法检测Bc1-2、Bax、caspase-3p17、CyclinD1、 MMP-2、MMP-9和E-cadherin的蛋白表达水平。
结果膀胱癌T24细胞可见naspin启动子甲基化DNA的扩增产物。加入不同浓度的甲基化抑制剂5-Aza-CdR后,maspin的mRNA和蛋白表达水平均呈明显增加,并具有浓度依赖性(P<0.05)；MTT实验结果证实T24细胞的增殖能力被明显抑制(P<0.05)；流式细胞仪检测发现T24细胞的凋亡明显增加(P<0.05)；细胞迁移实验和侵袭实验表明T24细胞的迁移和侵袭能力明显减弱(P<0.05)。Western blotting的结果显示CyclinD1、Bcl-2、MMP-2和MMP-9的蛋白表达水平显著下降,而Bax、caspase-3p17和E-cadherin的水平则显著增高(P<0.05)。
结论膀胱癌T24细胞maspin基因的启动子存在高甲基化状态。采用甲基化抑制剂5-Aza-CdR处理后,maspin的mRNA和蛋白表达水平均明显增加。maspin通过下调cyclinD1的表达,抑制T24细胞的增殖；通过上调促凋亡蛋白Bax和caspase-3p17的表达以及下调抗凋亡蛋白Bcl-2的表达,促进T24细胞的凋亡；通过下调MMP-2和MMP-9的表达以及上调E-cadherin的表达,抑制T24细胞的迁移和侵袭能力。
第三部分maspin与VEGF-C在膀胱癌中的表达及相关性研究
目的研究膀胱癌标本中maspin蛋白与VEGF-C蛋白表达的关系,并通过体外实验进一步验证。
方法采用免疫组化的方法研究53例膀胱癌患者的手术标本中VEGF-C蛋白和maspin蛋白的表达情况,并检验两者的相关性。采用Western blotting方法检测不同浓度的VEGF-C (0,50,100,200ng/mL)对maspin蛋白在T24细胞中的表达的影响。通过不同浓度的5-Aza-CdR(0,0.25,0.5,1,2μmol/L)激活naspin的表达,再采用Western blotting方法观察maspin对T24细胞中VEGF-C蛋白表达的影响,进一步在体外实验探讨其相关性。
结果VEGF-C蛋白在膀胱癌组织中的表达显著高于正常组织,而maspin蛋白的表达在膀胱癌组织中的表达则显著低于正常组织。53例膀胱癌标本的maspin蛋白与VEGF-C蛋白表达都与膀胱癌的临床分期、病理分级和淋巴结转移相关(P<0.05),与性别、年龄、肿瘤大小、肿瘤个数和发病次数均无明显相关(P>0.05)。maspin的表达与VEGF-C的表达呈负性相关,相关系数为-0.589(P<0.001)。VEGF-C作用于T24细胞后,maspin蛋白的表达明显下降；而当rmaspin蛋白的表达被激活后,VEGF-C蛋白的表达也显著减少。这两种效应均具有浓度依赖性(P<0.05)。
结论VEGF-C蛋白在膀胱癌组织中的表达显著高于正常膀胱组织,而maspin蛋白在膀胱癌组织中的表达则显著低于正常膀胱组织。maspin和VEGF-C蛋白都与膀胱癌的临床分期、分级和淋巴结转移的发生率具有统计学意义的关联,对膀胱癌的诊断和治疗具有重要的临床意义。maspin和VEGF-C在膀胱癌中的表达呈负性相关,两者之间的相互调控可能在膀胱癌的发展过程中起着重要作用。
Part one Study of the proteomic profile in bladder cancer T24cells after silencing VEGF-C
Objective To screen out the potential VEGF-C associated proteins invo-lved in malignant progression of the bladder cancer T24cells, in order to explore the functional mechanism of VEGF-C in bladder cancer.
Methods Lentivirus vector-based RNA interference (RNAi) technique was employed to diminish VEGF-C expression of bladder cancer T24cells. Then we performed comparative proteomics to explore differentially expressed proteins in T24cells with and without silencing VEGF-C, by fluorescence two-dimensional difference gel electrophoresis (2D-DIGE). These proteins are supposed to be potential VEGF-C associated proteins.
Results Twenty-five protein spots were found, and twenty-three proteins were identified finally. These proteins were grouped into different functional classes:cytoskeletal proteins, signal transduction proteins, molecular chaperones, cell proliferation and metastasis-related proteins, biosynthesis proteins, energy metabolism proteins and so on. Among them, ten proteins were overexpressed in RNAi group compared with Control group, and thirteen proteins were downregulated
Conclusions It's applicable for RNAi coupled with2D-DIGE to screen out the potential VEGF-C associated proteins from bladder cancer T24cells. They provide some new markers to uncovere the molecular mechanism of VEGF-C promoting malignant development of bladder cancer cells.
Part two The effects of maspin on the biologic behaviors of T24cells
Objective To explore the effects of maspin on the biologic behaviors of T24cells, such as proliferation, apoptosis, migration and invasion. The mechanism was also studied.
Methods Methylation status of maspin in T24cells was investigated by methylation-specific polymerase chain reaction (MSP). After treated with different concentrations of5-Aza-CdR (0,0.25,0.5,1,2μmol/L), Real Time Polymerase Chain Reaction (Real Time PCR) and Western blotting were carried out to examine mRNA expression and protein expression of maspin. Cell proliferation was evaluated by MTT assay. Flow cytometry was used to identify apoptosis rates. Migration and invasive ability were determined by the Transwell assay. Using the Western blotting analysis, the changes of CyclinD1, Bcl-2, Bax, caspase-3p17, MMP-2, MMP-9and E-cadherin expression were measured.
Results Promoter DNA methylation of maspin was observed in T24 cells. The expression levels of maspin mRNA and protein in T24cells were increased in a dose manner following treatment with increasing5-Aza-CdR (P<0.05). The proliferation, migration and invasion of cells were significantly inhibited with increasing5-Aza-CdR in a dose manner, whereas the apoptosis rate was greatly increased (P<0.05). These were associated with decreased expressions of CyclinD1, Bcl-2, MMP-2and MMP-9, and increased expressions of Bax, caspase-3p17and E-cadherin.
Conclusions Hypermethylation of maspin gene exist in bladder T24cells and its expression can be induced by treatment with5-Aza-CdR. Enhanced expression of maspin induced by5-Aza-CdR could obviously inhibit the proliferation, migration and invasion of T24cells, and promote the apoptosis. These were associated with reduced expressions of CyclinD1, Bcl-2, MMP-2and MMP-9, and increased expression of Bax, caspase-3p17and E-cadherin.
Part Three The relationship between maspin and VEGF-C expression in bladder cancer
Objective To explore the relationship between maspin and VEGF-C expression in bladder cancer tissues and validate it further in vitro.
Methods The expressions and relationship of maspin and VEGF-C in bladder cancer was examined by immunohistochemistry technique. Western blotting analysis was employed to measure the maspin protein expression of T24stimulating by different concentrations of VEGF-C (0,50,100,200ng/mL) in vitro. Then VEGF-C protein expression was also detected using western blotting in the presence of enhanced expression of maspin induced by increasing5-Aza-CdR (0,0.25,0.5,1,2μmol/L).
Results Among53specimens, the expression of VEGF-C in bladder cancer is obviously higher than that in the nomal tissues, whereas the expression of maspin in bladder cancer is significantly lower than that in the nomal tissues, maspin and VEGF-C are related to stage, grade and lymph node metastasis of bladder cancer (P<0.05), not the other features. There is an obvious inverse correlation between expression of maspin and VEGF-C protein, and the related coefficient was-0.589(P<0.001). Maspin protein expression appeared to decrease significantly with increasing concentrations of VEGF-C, and vice versa (P<0.05). These effects are both in dose manners.
Conclusion The expression of VEGF-C in bladder cancer is obviously higher than that in the nomal tissues, whereas the expression of maspin in bladder cancer is significantly lower than that in the nomal tissues. Maspin and VEGF-C are related to stage, grade and lymph node metastasis of bladder cancer, showing significant clinical relevance. There is an obvious inverse correlation between expression of maspin and VEGF-C protein, which may be important for the development of bladder cancer.
目的寻找在膀胱癌T24细胞中与VEGF-C基因功能相关的蛋白,为了解VEGF-C基因在膀胱癌的作用机制提供新的思路。
方法采用RNA干扰技术沉默人膀胱癌T24细胞中的VEGF-C基因,再抽提沉默组和对照组的肿瘤细胞全蛋白,利用荧光差异显示双向凝胶电泳技术获取蛋白质电泳图谱。通过对差异表达的蛋白质点定量和鉴定,筛选出与VEGF-C基因可能有相互作用的蛋白质。
结果沉默组和对照组细胞之间存在25个差异蛋白质点。经质谱鉴定后,23个蛋白质点被成功鉴定。这些蛋白质包括：细胞骨架蛋白、信号转导蛋白、分子伴侣、细胞增殖和转移相关蛋白、生物合成蛋白、能量代谢蛋白等。在这23个蛋白质中,10个蛋白质在沉默组中表达上调,另外13个蛋白质沉默组中表达下调。
结论联合应用RNA干扰技术和比较蛋白质组学方法,高通量筛选膀胱癌细胞中VEGF-C功能相关蛋白具有可行性。本研究发现了23个潜在的与VEGF-C功能相关的蛋白质,为进一步阐明VEGF-C促膀胱癌恶性发展的作用机制提供了新的线索和思路。
第二部分maspin对膀胱癌T24细胞生物学行为的影响和机制研究
目的研究maspin对膀胱癌T24细胞生物学行为的影响,并初步探讨其可能机制。
方法首先通过甲基化特异性PCR法检测naspin启动子在膀胱癌T24细胞中的甲基化状态,再利用Real Time PCR和Western blotting方法观察不同浓度的5-氮杂-2’-脱氧胞苷(5-aza-2'-deoxycytidine,5-Aza-CdR,0,0.25,0.5,1,2μmol/L)对naspin的mRNA和蛋白表达水平的影响。通过MTT实验观察maspin对T24细胞的增殖能力的影响,通过流式细胞仪观察maspin对T24细胞的凋亡的影响,通过迁移和侵袭实验观察maspin对T24细胞的迁移和侵袭能力的影响,并通过Western blotting方法检测Bc1-2、Bax、caspase-3p17、CyclinD1、 MMP-2、MMP-9和E-cadherin的蛋白表达水平。
结果膀胱癌T24细胞可见naspin启动子甲基化DNA的扩增产物。加入不同浓度的甲基化抑制剂5-Aza-CdR后,maspin的mRNA和蛋白表达水平均呈明显增加,并具有浓度依赖性(P<0.05)；MTT实验结果证实T24细胞的增殖能力被明显抑制(P<0.05)；流式细胞仪检测发现T24细胞的凋亡明显增加(P<0.05)；细胞迁移实验和侵袭实验表明T24细胞的迁移和侵袭能力明显减弱(P<0.05)。Western blotting的结果显示CyclinD1、Bcl-2、MMP-2和MMP-9的蛋白表达水平显著下降,而Bax、caspase-3p17和E-cadherin的水平则显著增高(P<0.05)。
结论膀胱癌T24细胞maspin基因的启动子存在高甲基化状态。采用甲基化抑制剂5-Aza-CdR处理后,maspin的mRNA和蛋白表达水平均明显增加。maspin通过下调cyclinD1的表达,抑制T24细胞的增殖；通过上调促凋亡蛋白Bax和caspase-3p17的表达以及下调抗凋亡蛋白Bcl-2的表达,促进T24细胞的凋亡；通过下调MMP-2和MMP-9的表达以及上调E-cadherin的表达,抑制T24细胞的迁移和侵袭能力。
第三部分maspin与VEGF-C在膀胱癌中的表达及相关性研究
目的研究膀胱癌标本中maspin蛋白与VEGF-C蛋白表达的关系,并通过体外实验进一步验证。
方法采用免疫组化的方法研究53例膀胱癌患者的手术标本中VEGF-C蛋白和maspin蛋白的表达情况,并检验两者的相关性。采用Western blotting方法检测不同浓度的VEGF-C (0,50,100,200ng/mL)对maspin蛋白在T24细胞中的表达的影响。通过不同浓度的5-Aza-CdR(0,0.25,0.5,1,2μmol/L)激活naspin的表达,再采用Western blotting方法观察maspin对T24细胞中VEGF-C蛋白表达的影响,进一步在体外实验探讨其相关性。
结果VEGF-C蛋白在膀胱癌组织中的表达显著高于正常组织,而maspin蛋白的表达在膀胱癌组织中的表达则显著低于正常组织。53例膀胱癌标本的maspin蛋白与VEGF-C蛋白表达都与膀胱癌的临床分期、病理分级和淋巴结转移相关(P<0.05),与性别、年龄、肿瘤大小、肿瘤个数和发病次数均无明显相关(P>0.05)。maspin的表达与VEGF-C的表达呈负性相关,相关系数为-0.589(P<0.001)。VEGF-C作用于T24细胞后,maspin蛋白的表达明显下降；而当rmaspin蛋白的表达被激活后,VEGF-C蛋白的表达也显著减少。这两种效应均具有浓度依赖性(P<0.05)。
结论VEGF-C蛋白在膀胱癌组织中的表达显著高于正常膀胱组织,而maspin蛋白在膀胱癌组织中的表达则显著低于正常膀胱组织。maspin和VEGF-C蛋白都与膀胱癌的临床分期、分级和淋巴结转移的发生率具有统计学意义的关联,对膀胱癌的诊断和治疗具有重要的临床意义。maspin和VEGF-C在膀胱癌中的表达呈负性相关,两者之间的相互调控可能在膀胱癌的发展过程中起着重要作用。
Part one Study of the proteomic profile in bladder cancer T24cells after silencing VEGF-C
Objective To screen out the potential VEGF-C associated proteins invo-lved in malignant progression of the bladder cancer T24cells, in order to explore the functional mechanism of VEGF-C in bladder cancer.
Methods Lentivirus vector-based RNA interference (RNAi) technique was employed to diminish VEGF-C expression of bladder cancer T24cells. Then we performed comparative proteomics to explore differentially expressed proteins in T24cells with and without silencing VEGF-C, by fluorescence two-dimensional difference gel electrophoresis (2D-DIGE). These proteins are supposed to be potential VEGF-C associated proteins.
Results Twenty-five protein spots were found, and twenty-three proteins were identified finally. These proteins were grouped into different functional classes:cytoskeletal proteins, signal transduction proteins, molecular chaperones, cell proliferation and metastasis-related proteins, biosynthesis proteins, energy metabolism proteins and so on. Among them, ten proteins were overexpressed in RNAi group compared with Control group, and thirteen proteins were downregulated
Conclusions It's applicable for RNAi coupled with2D-DIGE to screen out the potential VEGF-C associated proteins from bladder cancer T24cells. They provide some new markers to uncovere the molecular mechanism of VEGF-C promoting malignant development of bladder cancer cells.
Part two The effects of maspin on the biologic behaviors of T24cells
Objective To explore the effects of maspin on the biologic behaviors of T24cells, such as proliferation, apoptosis, migration and invasion. The mechanism was also studied.
Methods Methylation status of maspin in T24cells was investigated by methylation-specific polymerase chain reaction (MSP). After treated with different concentrations of5-Aza-CdR (0,0.25,0.5,1,2μmol/L), Real Time Polymerase Chain Reaction (Real Time PCR) and Western blotting were carried out to examine mRNA expression and protein expression of maspin. Cell proliferation was evaluated by MTT assay. Flow cytometry was used to identify apoptosis rates. Migration and invasive ability were determined by the Transwell assay. Using the Western blotting analysis, the changes of CyclinD1, Bcl-2, Bax, caspase-3p17, MMP-2, MMP-9and E-cadherin expression were measured.
Results Promoter DNA methylation of maspin was observed in T24 cells. The expression levels of maspin mRNA and protein in T24cells were increased in a dose manner following treatment with increasing5-Aza-CdR (P<0.05). The proliferation, migration and invasion of cells were significantly inhibited with increasing5-Aza-CdR in a dose manner, whereas the apoptosis rate was greatly increased (P<0.05). These were associated with decreased expressions of CyclinD1, Bcl-2, MMP-2and MMP-9, and increased expressions of Bax, caspase-3p17and E-cadherin.
Conclusions Hypermethylation of maspin gene exist in bladder T24cells and its expression can be induced by treatment with5-Aza-CdR. Enhanced expression of maspin induced by5-Aza-CdR could obviously inhibit the proliferation, migration and invasion of T24cells, and promote the apoptosis. These were associated with reduced expressions of CyclinD1, Bcl-2, MMP-2and MMP-9, and increased expression of Bax, caspase-3p17and E-cadherin.
Part Three The relationship between maspin and VEGF-C expression in bladder cancer
Objective To explore the relationship between maspin and VEGF-C expression in bladder cancer tissues and validate it further in vitro.
Methods The expressions and relationship of maspin and VEGF-C in bladder cancer was examined by immunohistochemistry technique. Western blotting analysis was employed to measure the maspin protein expression of T24stimulating by different concentrations of VEGF-C (0,50,100,200ng/mL) in vitro. Then VEGF-C protein expression was also detected using western blotting in the presence of enhanced expression of maspin induced by increasing5-Aza-CdR (0,0.25,0.5,1,2μmol/L).
Results Among53specimens, the expression of VEGF-C in bladder cancer is obviously higher than that in the nomal tissues, whereas the expression of maspin in bladder cancer is significantly lower than that in the nomal tissues, maspin and VEGF-C are related to stage, grade and lymph node metastasis of bladder cancer (P<0.05), not the other features. There is an obvious inverse correlation between expression of maspin and VEGF-C protein, and the related coefficient was-0.589(P<0.001). Maspin protein expression appeared to decrease significantly with increasing concentrations of VEGF-C, and vice versa (P<0.05). These effects are both in dose manners.
Conclusion The expression of VEGF-C in bladder cancer is obviously higher than that in the nomal tissues, whereas the expression of maspin in bladder cancer is significantly lower than that in the nomal tissues. Maspin and VEGF-C are related to stage, grade and lymph node metastasis of bladder cancer, showing significant clinical relevance. There is an obvious inverse correlation between expression of maspin and VEGF-C protein, which may be important for the development of bladder cancer.
引文
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