膀胱癌顺铂耐药与其基因甲基化相关性研究
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摘要
目的：
通过了解顺铂耐药膀胱癌细胞中DNA甲基化谱的改变，探索与发生顺铂耐药密切相关的基因的甲基化及其蛋白表达的变化，为阐明膀胱癌化疗耐药机制提供新的实验依据。
方法：
（1）顺铂耐药膀胱癌细胞株的建立：利用顺铂浓度梯度递增法(0.2-2.0mg/L)，在T24膀胱癌细胞中建立顺铂耐受的细胞株亚型（T24/DDP），并对细胞的各项生物学指标进行检测，包括顺铂敏感性、细胞形态学、细胞生长曲线及细胞周期等。
（2）顺铂耐药膀胱癌细胞DNA甲基化谱分析与耐药相关甲基化基因的筛选：DNA甲基化芯片对T24及T24/DDP细胞基因组的DNA甲基化谱进行分析，并通过统计学方法，筛选高甲基化，及低甲基化修饰基因。利用real time-PCR方法对筛选出的具有表达差异的甲基化修饰基因进行分析，并结合文献资料，最终采用MSP法，对筛选出的甲基化修饰基因进行进一步的验证分析。
（3）通过5-氮杂-2-脱氧核苷去甲基化了解顺铂耐药膀胱癌细胞生物学的作用；并对细胞生物学指标进行检测。
（4）采用5-氮杂-2-脱氧核苷去甲基化了解逆转顺铂耐药膀胱癌细胞的分子机制：利用real time-PCR及western blot方法，对T24/DDP及经5-氮杂-2-脱氧核苷去甲基化处理T24/DDP细胞中关键基因及其蛋白的表达进行分析。
结果：
（1）成功建立顺铂耐药的膀胱癌细胞（T24/DDP）： DDP敏感性实验表明，在20ug/ml浓度的DDP处理下，T24细胞死亡率接近100%，而同样浓度下顺铂耐受的细胞株亚型T24/DDP细胞的死亡率则是30%。细胞生长曲线表明，T24与T24/DDP细胞的倍增时间分别为72.5和90.2小时。细胞形态学观察表明，T24与T24/DDP细胞形态学无明显差异。细胞周期分析表明，T24/DDP细胞中G0/G1期细胞比例显著增加，G2/M期细胞下降。
（2）顺铂耐药膀胱癌细胞DNA甲基化差异基因筛选：利用DNA甲基化谱芯片对T24及T24/DDP两个细胞系的基因组DNA甲基化谱进行分析，发现1120个甲基化差异位点；并筛选出40个高甲基化，18个低甲基化修饰基因。然后通过realtime-PCR方法对该58个差异甲基化修饰基因的表达进行了分析，发现其中30个基因的表达有统计学差异。结合文献资料，又筛选出和本研究相关基因20个，采用MSP法，对这些基因的甲基化修饰在细胞水平上又进行了验证分析，最终筛选出与甲基化谱芯片结果一致的15种基因，包括14种高甲基化和1种低甲基化修饰基因。
（3）5-氮杂-2-脱氧核苷去甲基化对顺铂耐药膀胱癌细胞的生物学作用：经去甲基化处理后，之前发现的14种高甲基化修饰差异基因中的7种基因的高甲基化修饰被改变：ABCC6， CCNA1， HPP1， ITGA4， RASSF1A, RUNX3，TMS1。同时去甲基化处理后，T24/DDP细胞对于顺铂的敏感性显著提高、细胞凋亡比例增加、S期细胞比例显著增加。
（4）5-氮杂-2-脱氧核苷去甲基化逆转顺铂耐药膀胱癌细胞的分子机制研究：利用real time-PCR和western blot方法的分析结果表明，上述7种基因（ABCC6，CCNA1， HPP1， ITGA4， RASSF1A, RUNX3，TMS1），经5-氮杂-2-脱氧核苷去甲基化处理后，其mRNA及蛋白的表达水平显著增加。
结论：
（1）顺铂浓度梯度递增法所建立的T24/DDP细胞株对顺铂具有很好的耐受性，可以作为体外模型用于顺铂耐药机制的研究。
（2）膀胱癌细胞发生顺铂耐药时，细胞基因组存在广泛的DNA甲基化修饰改变。
（3）5μM5-氮杂-2-脱氧核苷处理T24/DDP细胞，能使部分高甲基化修饰基因发生去甲基化，而提高T24/DDP细胞对于顺铂的敏感性。
（4）ABCC6， CCNA1， HPP1， ITGA4， RASSF1A, RUNX3，TMS1等7种基因的甲基化修饰可能在介导顺铂耐受作用机制中发挥重要作用。
Objective: To investigate the DNA methylation profile of cisplatin-resistance inbladder cancer cell, and explore the alteration of genes and proteins which are involved incisplatin-resistance.
Methods:
(1) The build-up of cisplatin-resistant bladder cancer cells (T24/DDP): Thecisplatin-resistant bladder cancer cells were built up in T24bladder cancer cells (T24/DDP)with continued increasing of concentrations (0.2-2.0mg/L). After the built-up of T24/DDPcell line, a series of biological parameters were measured including cisplatin sensitivity,cellular morphology, growth curve and cell cycle.
(2) DNA methylation profile and selection of drug-resistant genes in T24/DDP cellline: The DNA methylation profile was conducted with DNA methylation chips in T24andT24/DDP cells, and genes with hypermethylation or hypomethylation were screened bystatistical methods. The mRNA expression of selected genes with altered methylation wasanalyzed with real time-PCR. Then, the methylation of these genes was further validatedwith methylation-specific PCR (MSP).
(3) The biological impacts of5-aza-dC on T24/DDP cells: The demethylation wasconducted in T24/DDP cells by5-aza-dC treatment. Then, a series of cellular biologicalparameters were measured.
(4) The molecular mechanisms of demethylation with5-aza-dC in T24/DDP cells:The expression of genes and proteins were analyzed with real time-PCR and western blotin T24/DDP cells treated by5-aza-dC.
Results:
(1) The cisplatin-resistant bladder cancer cells (T24/DDP) were successfully built upin T24cell line. T24cells were almost100%died of cisplatin treatment at theconcentration of20ug/ml, whereas it was only30%in T24/DDP cells. The doubling timeof T24and T24/DDP cells was72.5and90.2hours respectively. There was no obviousdifference in morphology between T24and T24/DDP cells. However, a decrease in numberof mitochondria was observed in T24/DDP cells. Moreover, T24/DDP cells showedsignificant increase in percentage of G0/G1and decrease in G2/M, compared to T24cells.
(2) There are1120sites with altered methylation in genome of T24/DDP cellscompared to T24cells. Then,40genes with hypermethylation and18genes withhypomethylation were identified with statistical methods. The mRNA expression of30genes among the identified58genes was significantly different between T24and T24/DDPcells with real time-PCR. On the basis of references, we validated the20genes with MSPand found that15genes showed consistent results with methylation chips, including14genes with hypermethylation and1with hypomethylation.
(3) We found that7out of14validated genes with hypermethylation weredemethylated by5-aza-dC, including ABCC6， CCNA1， HPP1， ITGA4， RASSF1A,RUNX3， and TMS1, while the methylation status of the rest8genes was not changed.Moreover, we found that5-aza-dC treatment resulted in increased sensitivity to cisplatin,and increase in percentage of cell apoptosis and S phage in T24/DDP cells.
(4) The mRNA and protein expression of the7genes were significantly enhancedafter treatment of5-aza-dC, including ABCC6， CCNA1， HPP1， ITGA4， RASSF1A,RUNX3，and TMS1.
Conclusions:
(1) T24/DDP cells show well resistance to cisplatin, suggesting that the method ofcontinued increasing in concentration of cisplatin is reliable for inducing cisplatin-resistantcells.
(2) There are substantial changes in DNA methylation status in genome DNA ofT24/DDP cells.
(3) Treatment of5-aza-dC (5μM) can demethylate genes with hypermethylationpartially in T24/DDP cells.
(4) It is postulated that7genes may play important roles in mediatingcisplatin-resistance in T24cells, including ABCC6， CCNA1， HPP1， ITGA4，RASSF1A, RUNX3，and TMS1.
通过了解顺铂耐药膀胱癌细胞中DNA甲基化谱的改变，探索与发生顺铂耐药密切相关的基因的甲基化及其蛋白表达的变化，为阐明膀胱癌化疗耐药机制提供新的实验依据。
方法：
（1）顺铂耐药膀胱癌细胞株的建立：利用顺铂浓度梯度递增法(0.2-2.0mg/L)，在T24膀胱癌细胞中建立顺铂耐受的细胞株亚型（T24/DDP），并对细胞的各项生物学指标进行检测，包括顺铂敏感性、细胞形态学、细胞生长曲线及细胞周期等。
（2）顺铂耐药膀胱癌细胞DNA甲基化谱分析与耐药相关甲基化基因的筛选：DNA甲基化芯片对T24及T24/DDP细胞基因组的DNA甲基化谱进行分析，并通过统计学方法，筛选高甲基化，及低甲基化修饰基因。利用real time-PCR方法对筛选出的具有表达差异的甲基化修饰基因进行分析，并结合文献资料，最终采用MSP法，对筛选出的甲基化修饰基因进行进一步的验证分析。
（3）通过5-氮杂-2-脱氧核苷去甲基化了解顺铂耐药膀胱癌细胞生物学的作用；并对细胞生物学指标进行检测。
（4）采用5-氮杂-2-脱氧核苷去甲基化了解逆转顺铂耐药膀胱癌细胞的分子机制：利用real time-PCR及western blot方法，对T24/DDP及经5-氮杂-2-脱氧核苷去甲基化处理T24/DDP细胞中关键基因及其蛋白的表达进行分析。
结果：
（1）成功建立顺铂耐药的膀胱癌细胞（T24/DDP）： DDP敏感性实验表明，在20ug/ml浓度的DDP处理下，T24细胞死亡率接近100%，而同样浓度下顺铂耐受的细胞株亚型T24/DDP细胞的死亡率则是30%。细胞生长曲线表明，T24与T24/DDP细胞的倍增时间分别为72.5和90.2小时。细胞形态学观察表明，T24与T24/DDP细胞形态学无明显差异。细胞周期分析表明，T24/DDP细胞中G0/G1期细胞比例显著增加，G2/M期细胞下降。
（2）顺铂耐药膀胱癌细胞DNA甲基化差异基因筛选：利用DNA甲基化谱芯片对T24及T24/DDP两个细胞系的基因组DNA甲基化谱进行分析，发现1120个甲基化差异位点；并筛选出40个高甲基化，18个低甲基化修饰基因。然后通过realtime-PCR方法对该58个差异甲基化修饰基因的表达进行了分析，发现其中30个基因的表达有统计学差异。结合文献资料，又筛选出和本研究相关基因20个，采用MSP法，对这些基因的甲基化修饰在细胞水平上又进行了验证分析，最终筛选出与甲基化谱芯片结果一致的15种基因，包括14种高甲基化和1种低甲基化修饰基因。
（3）5-氮杂-2-脱氧核苷去甲基化对顺铂耐药膀胱癌细胞的生物学作用：经去甲基化处理后，之前发现的14种高甲基化修饰差异基因中的7种基因的高甲基化修饰被改变：ABCC6， CCNA1， HPP1， ITGA4， RASSF1A, RUNX3，TMS1。同时去甲基化处理后，T24/DDP细胞对于顺铂的敏感性显著提高、细胞凋亡比例增加、S期细胞比例显著增加。
（4）5-氮杂-2-脱氧核苷去甲基化逆转顺铂耐药膀胱癌细胞的分子机制研究：利用real time-PCR和western blot方法的分析结果表明，上述7种基因（ABCC6，CCNA1， HPP1， ITGA4， RASSF1A, RUNX3，TMS1），经5-氮杂-2-脱氧核苷去甲基化处理后，其mRNA及蛋白的表达水平显著增加。
结论：
（1）顺铂浓度梯度递增法所建立的T24/DDP细胞株对顺铂具有很好的耐受性，可以作为体外模型用于顺铂耐药机制的研究。
（2）膀胱癌细胞发生顺铂耐药时，细胞基因组存在广泛的DNA甲基化修饰改变。
（3）5μM5-氮杂-2-脱氧核苷处理T24/DDP细胞，能使部分高甲基化修饰基因发生去甲基化，而提高T24/DDP细胞对于顺铂的敏感性。
（4）ABCC6， CCNA1， HPP1， ITGA4， RASSF1A, RUNX3，TMS1等7种基因的甲基化修饰可能在介导顺铂耐受作用机制中发挥重要作用。
Objective: To investigate the DNA methylation profile of cisplatin-resistance inbladder cancer cell, and explore the alteration of genes and proteins which are involved incisplatin-resistance.
Methods:
(1) The build-up of cisplatin-resistant bladder cancer cells (T24/DDP): Thecisplatin-resistant bladder cancer cells were built up in T24bladder cancer cells (T24/DDP)with continued increasing of concentrations (0.2-2.0mg/L). After the built-up of T24/DDPcell line, a series of biological parameters were measured including cisplatin sensitivity,cellular morphology, growth curve and cell cycle.
(2) DNA methylation profile and selection of drug-resistant genes in T24/DDP cellline: The DNA methylation profile was conducted with DNA methylation chips in T24andT24/DDP cells, and genes with hypermethylation or hypomethylation were screened bystatistical methods. The mRNA expression of selected genes with altered methylation wasanalyzed with real time-PCR. Then, the methylation of these genes was further validatedwith methylation-specific PCR (MSP).
(3) The biological impacts of5-aza-dC on T24/DDP cells: The demethylation wasconducted in T24/DDP cells by5-aza-dC treatment. Then, a series of cellular biologicalparameters were measured.
(4) The molecular mechanisms of demethylation with5-aza-dC in T24/DDP cells:The expression of genes and proteins were analyzed with real time-PCR and western blotin T24/DDP cells treated by5-aza-dC.
Results:
(1) The cisplatin-resistant bladder cancer cells (T24/DDP) were successfully built upin T24cell line. T24cells were almost100%died of cisplatin treatment at theconcentration of20ug/ml, whereas it was only30%in T24/DDP cells. The doubling timeof T24and T24/DDP cells was72.5and90.2hours respectively. There was no obviousdifference in morphology between T24and T24/DDP cells. However, a decrease in numberof mitochondria was observed in T24/DDP cells. Moreover, T24/DDP cells showedsignificant increase in percentage of G0/G1and decrease in G2/M, compared to T24cells.
(2) There are1120sites with altered methylation in genome of T24/DDP cellscompared to T24cells. Then,40genes with hypermethylation and18genes withhypomethylation were identified with statistical methods. The mRNA expression of30genes among the identified58genes was significantly different between T24and T24/DDPcells with real time-PCR. On the basis of references, we validated the20genes with MSPand found that15genes showed consistent results with methylation chips, including14genes with hypermethylation and1with hypomethylation.
(3) We found that7out of14validated genes with hypermethylation weredemethylated by5-aza-dC, including ABCC6， CCNA1， HPP1， ITGA4， RASSF1A,RUNX3， and TMS1, while the methylation status of the rest8genes was not changed.Moreover, we found that5-aza-dC treatment resulted in increased sensitivity to cisplatin,and increase in percentage of cell apoptosis and S phage in T24/DDP cells.
(4) The mRNA and protein expression of the7genes were significantly enhancedafter treatment of5-aza-dC, including ABCC6， CCNA1， HPP1， ITGA4， RASSF1A,RUNX3，and TMS1.
Conclusions:
(1) T24/DDP cells show well resistance to cisplatin, suggesting that the method ofcontinued increasing in concentration of cisplatin is reliable for inducing cisplatin-resistantcells.
(2) There are substantial changes in DNA methylation status in genome DNA ofT24/DDP cells.
(3) Treatment of5-aza-dC (5μM) can demethylate genes with hypermethylationpartially in T24/DDP cells.
(4) It is postulated that7genes may play important roles in mediatingcisplatin-resistance in T24cells, including ABCC6， CCNA1， HPP1， ITGA4，RASSF1A, RUNX3，and TMS1.
引文
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