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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma
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Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma

机译：衰老的肝，慢性肝炎和肝细胞癌中多种肿瘤抑制基因的异常甲基化

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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.
机译：DNA甲基化异常是肝细胞癌（HCC）中重要的表观遗传学改变。但是，人们对甲基化子表型和肝炎病毒的贡献所基于的分子过程知之甚少。当前的研究是对人类肝脏组织标本的全面甲基化分析。分析了总共176个肝脏组织（包括77对HCC和相匹配的非癌性肝和22个正常肝）的甲基化。量化了19种表观遗传标记的甲基化，其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。根据甲基化概况，将19个基因座分为3组。正常肝组织主要在第1组位点（HIC-1，CASP8，GSTP1，SOCS1，RASSF1A，p16，APC）显示甲基化，显着高于第2组（CDH1，RUNX3，RIZ1，SFRP2，MINT31）和第3组标记（COX2，MINT1，CACNA1G，RASSF2，MINT2，Reprimo3，DCC）（P <0.0001）。在第一组和第二组基因座中，非癌性肝均显示甲基化增加。与正常肝组织相比，HCV阳性肝脏的甲基化明显丰富。相反，在所有3个研究组中，每个部位的HCC均显示频繁的甲基化。然而，与HBV阳性和病毒阴性的癌症相比，第3组基因座在HCV阳性的癌症中显示出更高的致密性和频繁的甲基化程度（P <0.0001）。结论：肝癌中甲基化很常见，但以基因特异性和疾病特异性方式发生。甲基化分析使我们能够确定正常衰老的肝脏中通常存在异常的甲基化，并且随着慢性病毒感染的进展阶段而依次发展。最后，我们的数据提供了证据，表明HCV感染可能会加速甲基化过程，并提示随着持续的病毒感染和肝脏中的癌变，甲基化持续增加。

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