EBV相关胃癌抑癌基因甲基化状态的研究
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摘要
EB病毒(Epstein-Barr virus, EBV)是重要的DNA肿瘤病毒,与人类多种恶性肿瘤密切相关。DNA甲基化是目前最为前沿及研究最为深入的表观遗传学机制,其中抑癌基因(tumor suppressor genes, TSGs)启动子高度甲基化被认为是除突变和缺失以外抑癌基因功能失活的关键机制。
目的筛选鉴定EBV阳性胃癌细胞系中由于甲基化而沉默的抑癌基因。
方法选取EBV阳性(GT38、PT和SNU719)和阴性(SGC7901)胃癌细胞系,用5-氮杂-2'-脱氧胞苷(5-Aza-CdR)处理,然后采用Agilent人类全基因组表达谱芯片(4x44K)检测处理前后基因表达水平。采用荧光实时定量PCR法(Real-time quantitative PCR, real-time qPCR)验证基因芯片结果,甲基化特异性PCR (Methylation-Specific PCR,MSP)及亚硫酸氢盐基因组测序法(Bisulfite genomic sequencing, BGS)检测部分基因启动子区域CpG岛甲基化情况。
结果①芯片检测结果显示,5-Aza-CdR处理后表达显著上调的基因：GT38细胞系860条；PT细胞系804条；SNU719细胞系1099条；SGC7901细胞系5924条。表达显著下调的基因：GT38细胞系679条；PT细胞系667条；SNU719细胞系667条；SGC7901细胞系5882条。②三种EBV阳性胃癌细胞系(GT38、PT和SNU719)中筛选出42条共表达上调基因,与SGC7901处理后表达上调基因比较,筛选出差异表达基因19条。③采用real-time qPCR检测细胞5-Aza-CdR处理前后差异表达基因(H19、LOXL1、ARMCX2、LXN、CDH3和MMP7)的表达水平,结果与基因芯片分析结果基本一致。④MSP和BGS法检测结果显示在EBV阳性细胞系中LOXL1基因启动子均存在不同程度的甲基化,且在GT38和PT中呈完全甲基化,SGC7901和HGC-27中未发生甲基化,提示该基因为因甲基化而沉默的候选抑癌基因。⑤EBVaGC和EBVnGC组织中LOXL1基因启动子甲基化状态有差别,EBVaGC组织中其甲基化程度明显高于EBVnGC。
结论①表达谱芯片初步筛选出19条EBV诱导甲基化而表达下调的基因,其基因调控区甲基化导致表达下调,甲基化转移酶抑制剂可激活这些基因表达,它们在EBVaGC发病中可能具有重要作用。②候选抑癌基因LOXL1启动子区均呈高甲基化状态,表明EBV是导致LOXL1基因调控区域甲基化的重要原因；启动子CpG岛发生异常甲基化进而引起抑癌基因失活可能是EBV参与EBVaGC发生的一种机制。
Epstein-Barr virus (EBV) is an important DNA virus, which has a close relationship with many kinds of human malignant tumor. DNA methylation is the most cutting-edge and the most studied epigenetic mechanism. Besides mutation and deletion, the hypermethylation of tumor suppressor gene promoter is considered the key mechanism of inactivation in the tumor.
Objective To identify the methylation silenced tumor suppressor genes in EBVaGC.
Methods Agilent Human Whole Genome Expression Profiling (4×44K) chips were used to compare the changes in gene expression profiles following the treatment of 5-Aza-CdR in EBVaGC (PT、GT38 and SNU719) and EBVnGC (SGC7901) cell lines. real-time qPCR was used to validate the results of microarray, MSP and BGS was adopted to detect the methylation levels of gene promoters.
Results①T he differential expression genes were identified by microarray analysis, up-regulated genes:GT38,860 genes; PT,804 genes; SNU719,1099 genes; SGC7901,5924 genes. Down-regulated genes:GT38,679 genes; PT,667 genes; SNU719,667 genes; SGC7901,5882 genes.②A total of 42 up-regulated genes were found in three EBVaGC (PT, GT38 and SNU719) cell lines. The functions of these genes were involved in tumor suppression, immunity, cell adhesion, cell cycle, cell proliferation, apoptosis, signal transduction and etc. Compared to the EBVnGC cell lines,19 differential genes were found in these 42 selected genes.③The expression levels of 6 differential genes (H19, LOXL1, ARMCX2, LXN, CDH3 and MMP7) in 5-Aza-CdR treated cells were confirmed by real-time qPCR, which were consistent with the results of microarray.④The methylation status of LOXL1 was detected by MSP and BGS in cell lines. The results showed that the promoter of LOXL1 was hypermethylation in different degrees, suggesting that this gene as candidate methylation silenced tumor suppressor gene.⑤The methylation rates of LOXL1 in EBVaGC were significantly higher than those in EBVnGC.
Conclusion①The expression chip screens 19 genes silenced by methylation and reactivated by 5-Aza-CdR in EBVaGC. These genes may play an important role in the pathogenesis of EBVaGC.②The promoter methylation of LOXL1 is an important regulation mechanism of gene expression. It suggested LOXL-1 is a methylation silenced tumor suppressor gene in EBVaGC. The hypermethylation of tumor suppressor gene promoter induced by EBV may play an important role in the pathogenesis of EBVaGC
目的筛选鉴定EBV阳性胃癌细胞系中由于甲基化而沉默的抑癌基因。
方法选取EBV阳性(GT38、PT和SNU719)和阴性(SGC7901)胃癌细胞系,用5-氮杂-2'-脱氧胞苷(5-Aza-CdR)处理,然后采用Agilent人类全基因组表达谱芯片(4x44K)检测处理前后基因表达水平。采用荧光实时定量PCR法(Real-time quantitative PCR, real-time qPCR)验证基因芯片结果,甲基化特异性PCR (Methylation-Specific PCR,MSP)及亚硫酸氢盐基因组测序法(Bisulfite genomic sequencing, BGS)检测部分基因启动子区域CpG岛甲基化情况。
结果①芯片检测结果显示,5-Aza-CdR处理后表达显著上调的基因：GT38细胞系860条；PT细胞系804条；SNU719细胞系1099条；SGC7901细胞系5924条。表达显著下调的基因：GT38细胞系679条；PT细胞系667条；SNU719细胞系667条；SGC7901细胞系5882条。②三种EBV阳性胃癌细胞系(GT38、PT和SNU719)中筛选出42条共表达上调基因,与SGC7901处理后表达上调基因比较,筛选出差异表达基因19条。③采用real-time qPCR检测细胞5-Aza-CdR处理前后差异表达基因(H19、LOXL1、ARMCX2、LXN、CDH3和MMP7)的表达水平,结果与基因芯片分析结果基本一致。④MSP和BGS法检测结果显示在EBV阳性细胞系中LOXL1基因启动子均存在不同程度的甲基化,且在GT38和PT中呈完全甲基化,SGC7901和HGC-27中未发生甲基化,提示该基因为因甲基化而沉默的候选抑癌基因。⑤EBVaGC和EBVnGC组织中LOXL1基因启动子甲基化状态有差别,EBVaGC组织中其甲基化程度明显高于EBVnGC。
结论①表达谱芯片初步筛选出19条EBV诱导甲基化而表达下调的基因,其基因调控区甲基化导致表达下调,甲基化转移酶抑制剂可激活这些基因表达,它们在EBVaGC发病中可能具有重要作用。②候选抑癌基因LOXL1启动子区均呈高甲基化状态,表明EBV是导致LOXL1基因调控区域甲基化的重要原因；启动子CpG岛发生异常甲基化进而引起抑癌基因失活可能是EBV参与EBVaGC发生的一种机制。
Epstein-Barr virus (EBV) is an important DNA virus, which has a close relationship with many kinds of human malignant tumor. DNA methylation is the most cutting-edge and the most studied epigenetic mechanism. Besides mutation and deletion, the hypermethylation of tumor suppressor gene promoter is considered the key mechanism of inactivation in the tumor.
Objective To identify the methylation silenced tumor suppressor genes in EBVaGC.
Methods Agilent Human Whole Genome Expression Profiling (4×44K) chips were used to compare the changes in gene expression profiles following the treatment of 5-Aza-CdR in EBVaGC (PT、GT38 and SNU719) and EBVnGC (SGC7901) cell lines. real-time qPCR was used to validate the results of microarray, MSP and BGS was adopted to detect the methylation levels of gene promoters.
Results①T he differential expression genes were identified by microarray analysis, up-regulated genes:GT38,860 genes; PT,804 genes; SNU719,1099 genes; SGC7901,5924 genes. Down-regulated genes:GT38,679 genes; PT,667 genes; SNU719,667 genes; SGC7901,5882 genes.②A total of 42 up-regulated genes were found in three EBVaGC (PT, GT38 and SNU719) cell lines. The functions of these genes were involved in tumor suppression, immunity, cell adhesion, cell cycle, cell proliferation, apoptosis, signal transduction and etc. Compared to the EBVnGC cell lines,19 differential genes were found in these 42 selected genes.③The expression levels of 6 differential genes (H19, LOXL1, ARMCX2, LXN, CDH3 and MMP7) in 5-Aza-CdR treated cells were confirmed by real-time qPCR, which were consistent with the results of microarray.④The methylation status of LOXL1 was detected by MSP and BGS in cell lines. The results showed that the promoter of LOXL1 was hypermethylation in different degrees, suggesting that this gene as candidate methylation silenced tumor suppressor gene.⑤The methylation rates of LOXL1 in EBVaGC were significantly higher than those in EBVnGC.
Conclusion①The expression chip screens 19 genes silenced by methylation and reactivated by 5-Aza-CdR in EBVaGC. These genes may play an important role in the pathogenesis of EBVaGC.②The promoter methylation of LOXL1 is an important regulation mechanism of gene expression. It suggested LOXL-1 is a methylation silenced tumor suppressor gene in EBVaGC. The hypermethylation of tumor suppressor gene promoter induced by EBV may play an important role in the pathogenesis of EBVaGC
引文
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