Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma
Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma
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DOI：
10.1002/hep.22110
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发表时间：
2008-03-01
期刊：
影响因子：
13.5
通讯作者：
Goell, Ajay
中科院分区：
文献类型：
--
作者：
Nishida, Naoshi;Nagasaka, Takeshi;Goell, Ajay
DNA甲基化异常是肝细胞癌中一种重要的表观遗传改变。然而，甲基化表型背后的分子过程和肝炎病毒的贡献尚不清楚。目前的研究是对人肝组织标本进行全面的甲基化分析。总共176个肝脏组织，包括77对hcc和匹配的非癌性肝脏和22个正常肝脏，被分析甲基化。19个表观遗传标记的甲基化被量化，结果与不同的疾病状态以及是否存在乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）感染相关。根据甲基化谱，将这19个位点分为3组。正常肝组织甲基化主要发生在1组位点（HIC-1、CASP8、GSTP1、SOCS1、RASSF1A、p16、APC），显著高于2组位点（CDH1、RUNX3、RIZ1、SFRP2、MINT31）和3组位点（COX2、MINT1、CACNA1G、RASSF2、MINT2、primo3、DCC） （P < 0.0001）。非癌性肝脏在I组和2组位点均显示甲基化增加。与正常肝组织相比，hcv阳性肝脏的甲基化明显更丰富。相反，在所有3组中，HCC的每个位点都显示频繁的甲基化。然而，与hbv阳性癌症和病毒阴性癌症相比，3组位点在hcv阳性癌症中显示出更密集和频繁的甲基化（P < 0.0001）。结论：甲基化在HCC中是常见的，但以基因特异性和疾病特异性的方式发生。甲基化分析使我们能够确定异常甲基化通常存在于正常衰老的肝脏中，并随着慢性病毒感染的进展而依次进展。最后，我们的数据提供了证据，表明HCV感染可能加速甲基化过程，并提示甲基化持续增加，持续病毒感染和肝脏癌变。
Aberrant DNA methylation is an important epigenetic alteration in hepatocellular carcinoma (HCC). However, the molecular processes underlying the methylator phenotype and the contribution of hepatitis viruses are poorly understood. The current study is a comprehensive methylation analysis of human liver tissue specimens. A total of 176 liver tissues, including 77 pairs of HCCs and matching noncancerous liver and 22 normal livers, were analyzed for methylation. Methylation of 19 epigenetic markers was quantified, and the results were correlated with different disease states and the presence or absence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Based on methylation profiles, the 19 loci were categorized into 3 groups. Normal liver tissues showed methylation primarily in group 1 loci (HIC-1, CASP8, GSTP1, SOCS1, RASSF1A, p16, APC), which was significantly higher than group 2 (CDH1, RUNX3, RIZ1, SFRP2, MINT31) and group 3 markers (COX2, MINT1, CACNA1G, RASSF2, MINT2, Reprimo3, DCC) (P < 0.0001). Noncancerous livers demonstrated increased methylation in both group I and group 2 loci. Methylation was significantly more abundant in HCV-positive livers compared with normal liver tissues. Conversely, HCC showed frequent methylation at each locus investigated in all 3 groups. However, the group 3 loci showed more dense and frequent methylation in HCV-positive cancers compared with both HBV-positive cancers and virus-negative cancers (P < 0.0001). Conclusion: Methylation in HCC is frequent but occurs in a gene-specific and disease-specific manner. Methylation profiling allowed us to determine that aberrant methylation is commonly present in normal aging livers, and sequentially progresses with advancing stages of chronic viral infection. Finally, our data provide evidence that HCV infection may accelerate the methylation process and suggests a continuum of increasing methylation with persistent viral infection and carcinogenesis in the liver.