DR4?DR5基因甲基化对膀胱癌TRAIL耐受的影响研究
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南京医科大学科技发展基金重点项目(06NMUZ036)


Relationship between TRAIL resistance and methylation status of DR4 and DR5
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    目的:探讨膀胱癌细胞中DR4-DR5甲基化状态以及与肿瘤坏死因子相关凋亡诱导配体(TRAIL)耐受间的关系-方法:采用RT-PCR技术检测膀胱癌T24细胞-BIU87细胞表面DR4-DR5 mRNA表达,对低表达或无表达DR4-DR5膀胱癌细胞采用甲基化特异性PCR(MSP)检测DR4-DR5启动子甲基化状态-同时应用流式细胞仪检测TRAIL组以及TRAIL+5-氮杂胞苷组细胞凋亡状态-结果:RT-PCR示膀胱癌T24细胞无DR4-DR5表达,MSP法研究显示:DR4-DR5基因呈甲基化状态,对TRAIL诱导的凋亡表现为耐受状态(100 ng/ml TRAIL,凋亡率7.6%),经去甲基化试剂5-氮杂胞苷处理,T24细胞DR4-DR5表达随时间而增加,100 ng/ml TRAIL,凋亡率达29.2%;BIU-87细胞表达DR4-DR5并对TRAIL敏感(100 ng/ml TRAIL凋亡率30.4%),应用5-氮杂胞苷处理BIU87细胞,DR4-DR5表达无差异,100 ng/ml TRAIL,细胞凋亡率31.7%,MSP法检测DR4-DR5基因呈非甲基化状态-结论:膀胱癌T24细胞DR4-DR5启动子区域甲基化与TRAIL耐受有关,去甲基化可逆转上述耐受状态,可为TRAIL的下一步临床应用提供基础研究资料-

    Abstract:

    Objective:To investigate the relationship between resistance to TRAIL and methylation status of DR4 and DR5 in bladder cancer cell lines. Methods:T24 and BIU87 bladder cancer cell lines were employed in the study of mRNA expression DR4 and DR5 inbladder cancer cells were detected using reverse transcription polymerase chain reaction(RT-PCR). DNA methylation status of wes examined by methylation specific polymerase chain reaction(MSP) in bladder cancer cells with low expression of DR4 and DR5 mRNA. Furthermore,bladder cancer cells were exposed to TRAIL and TRAIL combined 5-aza-2,-deoxycytidine(AzadC) to measure cancer cells growth and apoptosis by Flow Cytometry. Results:No DR4 and DR5 expression were detected in T24 cell line by RT-PCR. The methylation status was determined and correlated with the expression pattern. We observed DR4 and DR5 promoter hypermethylation. In contrast,DR4 and DR5 hypermethylation could not be found in BIU87 cell line which remained DR4 and DR5 expression. The apoptosis rates of T24, BIU87 bladder cancer cells treated with 100 ng/ml TRAIL singly were 7.6%, 30.4% respectively,which had significant difference compared with the groups without treatment(P < 0.05). However the apoptosis rates of T24 and BIU87 cell lines treated by 100 ng/ml TRAIL combined with 5 μmol/L AzadC reached 29.2%,31.7% respectively. Conclusion:Our findings showed a functional relevance of the DR4,DR5 expression in T24 cell line and suggested a substantial contribution of DR4,DR5 hypermethylation and consequent loss of DR4,DR5 expression in bladder cancer.

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王 军,贾瑞鹏,许露伟,贺兴军,王书奎. DR4?DR5基因甲基化对膀胱癌TRAIL耐受的影响研究[J].南京医科大学学报(自然科学版),2009,29(7):958-962

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  • 收稿日期:2009-02-11
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