DNA 甲基化和基因表达谱显示肝癌中存在新的调控途径。
DNA methylation and gene expression profiles show novel regulatory pathways in hepatocellular carcinoma.
机构信息
Department of Medicine, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
Department of Surgery, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
出版信息
Clin Epigenetics. 2015 Apr 14;7(1):43. doi: 10.1186/s13148-015-0077-1. eCollection 2015.
BACKGROUND
Alcohol is a well-known risk factor for hepatocellular carcinoma (HCC), but the mechanisms underlying the alcohol-related hepatocarcinogenesis are still poorly understood. Alcohol alters the provision of methyl groups within the hepatic one-carbon metabolism, possibly inducing aberrant DNA methylation. Whether specific pathways are epigenetically regulated in alcohol-associated HCC is, however, unknown. The aim of the present study was to investigate the genome-wide promoter DNA methylation and gene expression profiles in non-viral, alcohol-associated HCC. From eight HCC patients undergoing curative surgery, array-based DNA methylation and gene expression data of all annotated genes were analyzed by comparing HCC tissue and homologous cancer-free liver tissue.
RESULTS
After merging the DNA methylation with gene expression data, we identified 159 hypermethylated-repressed, 30 hypomethylated-induced, 49 hypermethylated-induced, and 56 hypomethylated-repressed genes. Notably, promoter DNA methylation emerged as a novel regulatory mechanism for the transcriptional repression of genes controlling the retinol metabolism (ADH1A, ADH1B, ADH6, CYP3A43, CYP4A22, RDH16), iron homeostasis (HAMP), one-carbon metabolism (SHMT1), and genes with a putative, newly identified function as tumor suppressors (FAM107A, IGFALS, MT1G, MT1H, RNF180).
CONCLUSIONS
A genome-wide DNA methylation approach merged with array-based gene expression profiles allowed identifying a number of novel, epigenetically regulated candidate tumor-suppressor genes in alcohol-associated hepatocarcinogenesis. Retinol metabolism genes and SHMT1 are also epigenetically regulated through promoter DNA methylation in alcohol-associated HCC. Due to the reversibility of epigenetic mechanisms by environmental/nutritional factors, these findings may open up to novel interventional strategies for hepatocarcinogenesis prevention in HCC related to alcohol, a modifiable dietary component.
背景
酒精是肝细胞癌（HCC）的已知危险因素，但酒精相关的肝癌发生机制仍知之甚少。酒精改变了肝脏一碳代谢中甲基的供应，可能导致异常的 DNA 甲基化。然而，在酒精相关的 HCC 中，是否有特定的途径受到表观遗传调控尚不清楚。本研究旨在研究非病毒性、酒精相关 HCC 中的全基因组启动子 DNA 甲基化和基因表达谱。从 8 名接受根治性手术的 HCC 患者中，通过比较 HCC 组织和同源无癌肝组织，分析了基于阵列的 DNA 甲基化和所有注释基因的基因表达数据。
结果
将 DNA 甲基化与基因表达数据合并后，我们鉴定出 159 个高甲基化抑制、30 个低甲基化诱导、49 个高甲基化诱导和 56 个低甲基化抑制基因。值得注意的是，启动子 DNA 甲基化成为控制视黄醇代谢（ADH1A、ADH1B、ADH6、CYP3A43、CYP4A22、RDH16）、铁稳态（HAMP）、一碳代谢（SHMT1）和具有潜在新功能的基因转录抑制的新调节机制，作为肿瘤抑制基因（FAM107A、IGFALS、MT1G、MT1H、RNF180）。
结论
全基因组 DNA 甲基化方法与基于阵列的基因表达谱相结合，可在酒精相关肝癌发生中鉴定出许多新的、受表观遗传调控的候选肿瘤抑制基因。视黄醇代谢基因和 SHMT1 也通过酒精相关 HCC 中的启动子 DNA 甲基化受到表观遗传调控。由于环境/营养因素可逆转表观遗传机制，这些发现可能为预防与酒精相关的 HCC 中的肝癌发生提供新的干预策略，酒精是一种可改变的饮食成分。
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