Excessive activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide 2 (APOBEC2) contributes to liver and lung tumorigenesis
Excessive activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide 2 (APOBEC2) contributes to liver and lung tumorigenesis
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DOI：
10.1002/ijc.26114
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发表时间：
2012-03-15
影响因子：
6.4
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
--
作者：
Okuyama, Shunsuke;Marusawa, Hiroyuki;Chiba, Tsutomu
载脂蛋白B mRNA编辑酶催化多肽2（APOBEC 2）最初被鉴定为具有推定的核苷酸编辑活性的胞苷脱氨酶家族的成员。为了阐明APOBEC 2的生理和病理作用以及靶核苷酸，我们建立了APOBEC 2转基因小鼠模型，并研究了APOBEC 2表达是否会引起宿主DNA或RNA序列的核苷酸改变。序列分析显示，APOBEC 2在肝脏中的组成性表达导致真核生物翻译起始因子4 γ 2（Eif 4g 2）和磷酸酶和张力蛋白同源物（PTEN）基因转录物中核苷酸改变的频率显着较高。在72周龄时，20只APOBEC 2转基因小鼠中有2只发生肝细胞癌。此外，组成型APOBEC 2表达导致分析的20只转基因小鼠中有7只发生肺肿瘤。结合促炎细胞因子肿瘤坏死因子-a诱导APOBEC 2在肝细胞中异位表达的事实，我们的研究结果表明，异常APOBEC 2表达导致特定靶基因转录物的核苷酸改变，并可能通过肝脏炎症参与人肝细胞癌的发展。
Apolipoprotein B mRNA editing enzyme catalytic polypeptide 2 (APOBEC2) was originally identified as a member of the cytidine deaminase family with putative nucleotide editing activity. To clarify the physiologic and pathologic roles, and the target nucleotide of APOBEC2, we established an APOBEC2 transgenic mouse model and investigated whether APOBEC2 expression causes nucleotide alterations in host DNA or RNA sequences. Sequence analyses revealed that constitutive expression of APOBEC2 in the liver resulted in significantly high frequencies of nucleotide alterations in the transcripts of eukaryotic translation initiation factor 4 gamma 2 (Eif4g2) and phosphatase and tensin homolog (PTEN) genes. Hepatocellular carcinoma developed in 2 of 20 APOBEC2 transgenic mice at 72 weeks of age. In addition, constitutive APOBEC2 expression caused lung tumors in 7 of 20 transgenic mice analyzed. Together with the fact that the proinflammatory cytokine tumor necrosis factor-a induces ectopic expression of APOBEC2 in hepatocytes, our findings indicate that aberrant APOBEC2 expression causes nucleotide alterations in the transcripts of the specific target gene and could be involved in the development of human hepatocellular carcinoma through hepatic inflammation.