Methylation of the Constitutive Androstane Receptor Is Involved in the Suppression of CYP2C19 in Hepatitis B Virus-Associated Hepatocellular Carcinoma
Methylation of the Constitutive Androstane Receptor Is Involved in the Suppression of CYP2C19 in Hepatitis B Virus-Associated Hepatocellular Carcinoma
复制标题
组成性雄甾烷受体的甲基化参与乙型肝炎病毒相关肝细胞癌中 CYP2C19 的抑制
DOI：
10.1124/dmd.116.070243
复制
发表时间：
2016-10-01
影响因子：
3.9
通讯作者：
Chen, Shuqing
中科院分区：
文献类型：
--
作者：
Tang, Xiaojing;Ge, Lele;Chen, Shuqing
肝细胞癌（HCC）是最危险的恶性肿瘤之一，其发病率和死亡率不断增加，是一个重大的国际健康问题。已知 HCC 进展涉及全基因组表观遗传修饰的改变，导致异常的基因表达模式。据报道，细胞色素 P450 超家族的重要成员 CYP2C19 的活性在 HCC 中受到损害，但其潜在机制仍不清楚。为了了解 HCC 中的表观遗传修饰是否与 CYP2C19 活性的变化相关，我们使用从乙型肝炎病毒 (HBV) 感染患者的原代肝细胞和配对肿瘤与非肿瘤肝组织中提取的 mRNA，通过定量实时聚合酶链反应评估了 CYP2C19 及其转录因子的表达水平。通过亚硫酸氢盐测序和甲基化特异性聚合酶链反应检查 DNA 甲基化。我们的结果表明，CYP2C19 可以通过组成型雄甾烷受体 (CAR) 的 e-box 甲基化来调节。 HBV感染的HCC患者肿瘤组织中CYP2C19表达的降低与CAR的表达抑制和启动子高甲基化高度相关。我们的研究表明，异常的 CAR 甲基化参与 HBV 相关 HCC 中 CYP2C19 的调节，并可能在肝脏肿瘤发生中发挥作用。
Hepatocellular carcinoma (HCC), one of the most dangerous malignancies with an increasing incidence and a high mortality rate, represents a major international health problem. HCC progression is known to involve genome-wide alteration of epigenetic modifications, leading to aberrant gene expression patterns. The activity of CYP2C19, an important member of the cytochrome P450 superfamily, was reported to be compromised in HCC, but the underlying mechanism remains unclear. To understand whether epigenetic modification in HCC is associated with a change in CYP2C19 activity, we evaluated the expression levels of CYP2C19 and its transcription factors by quantitative real-time polymerase chain reaction using mRNA extracted from both primary hepatocytes and paired tumor versus nontumor liver tissues of patients infected with hepatitis B virus (HBV). DNA methylation was examined by bisulfite sequencing and methylation-specific polymerase chain reaction. Our results indicated that CYP2C19 could be regulated by e-box methylation of the constitutive androstane receptor (CAR). Decreased CYP2C19 expression in tumorous tissues of HBV-infected patients with HCC was highly correlated with suppressed expression and promoter hypermethylation of CAR. Our study demonstrates that aberrant CAR methylation is involved in CYP2C19 regulation in HBV-related HCC and may play a role in liver tumorigenesis.