Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis.
Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis.
复制标题
苯巴比妥促进肝肿瘤发生过程中孤儿核受体组成型活性/雄甾烷受体介导的 DNA 甲基化改变。
DOI：
10.1093/toxsci/kfl188
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Goodman,JayI
中科院分区：
文献类型：
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作者：
Phillips,JenniferM;Yamamoto,Yukio;Negishi,Masahiko;Maronpot,RobertR;Goodman,JayI
DNA甲基化改变是一种表观遗传机制，在肿瘤发生过程中起着关键作用，而非遗传毒性的啮齿类动物肝癌原苯巴比妥（PB）改变了小鼠肝脏DNA的甲基化状态。组成型活性/雄烷核受体（CAR）介导了PB诱导的肝脏基因表达变化的一半，并且对于PB处理小鼠的肝脏肿瘤促进至关重要。在此，利用涉及甲基化敏感性限制性消化、任意引物PCR和毛细管电泳的技术来检测CAR野生型（WT）小鼠中PB诱导的DNA甲基化改变（RAM）区域，所述CAR野生型（WT）小鼠对PB和抗性CAR敲除（KO）小鼠的促进敏感。CAR WT小鼠在PB治疗23周后发生癌前病变（癌前病变），32周后发生肝肿瘤，而CAR KO小鼠没有发生肿瘤（Y. Yamamoto等人，64，7197-7200）。我们的目标是通过比较在敏感和耐药小鼠组中形成的RAM来辨别那些在肿瘤形成中起重要作用的RAM。使用这种新方法，与CAR KO，23周PB处理的组织相比，在癌前病变中鉴定了42种独特的RAM。在这42个RAM中，14个携带到肿瘤组织，另外，在肿瘤组织中观察到总共104个独特RAM。这些结果表明，在敏感的CAR WT小鼠中存在独特的RAM，并且其中一部分在癌前组织和肿瘤组织中可见。我们假设这些独特的RAM可能促进肿瘤发生过程，这些数据支持DNA甲基化在PB诱导的肿瘤发生中起着致病作用的观点。
Altered DNA methylation is an epigenetic mechanism that plays a key role in the carcinogenesis process, and the nongenotoxic rodent hepatocarcinogen phenobarbital (PB) alters the methylation status of DNA in mouse liver. The constitutive active/androstane nuclear receptor (CAR) mediates half of the PB-induced hepatic gene expression changes and it is essential for liver tumor promotion in PB-treated mice. Here, a technique involving methylation-sensitive restriction digestion, arbitrarily primed PCR, and capillary electrophoresis was utilized to detect PB-induced regions of altered DNA methylation (RAMs) in CAR wildtype (WT) mice that are sensitive to promotion by PB and resistant CAR knockout (KO) mice. The CAR WT mice developed preneoplastic lesions after 23 weeks of PB treatment (precancerous) and liver tumors after 32 weeks, while the CAR KO mice did not develop tumors (Y. Yamamoto,et al., 2004,Cancer Res.64, 7197–7200). Our goal was to discern those RAMs which are playing important roles in tumor formation by comparing the RAMs that form in sensitive and resistant groups of mice. Using this novel approach, 42 unique RAMs were identified in the precancerous as compared to the CAR KO, 23-week PB-treated tissue. Of these 42 RAMs, 14 carried forward to the tumor tissue, and additionally, 104 total unique RAMs were observed in the tumor tissue. These results indicate that there are unique RAMs occurring in the sensitive CAR WT mice and that a portion of these are seen in both the precancerous and tumor tissue. We hypothesize that these unique RAMs may be facilitating the tumorigenesis process, and these data support the view that DNA methylation plays a causative role in PB-induced tumorigenesis.