Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis
Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis
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DOI：
10.1093/carcin/bgv065
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发表时间：
2015-08-01
期刊：
影响因子：
4.7
通讯作者：
Marusawa, Hiroyuki
中科院分区：
文献类型：
--
作者：
Matsumoto, Tomonori;Shimizu, Takahiro;Marusawa, Hiroyuki
慢性炎症触发DNA突变酶（活化诱导的胞苷脱氨酶（AID））的异常表达，并通过遗传畸变的积累促成肿瘤发生。为了进一步了解炎症介导的致癌所需的遗传毒性事件，我们研究了慢性炎症在组成性AID表达的肝脏中出现遗传畸变中的作用。在野生型（WT）和AID转基因（Tg）小鼠中，低剂量浓度的硫代乙酰胺（TAA）治疗引起了极轻微的肝脏炎症。在6个月的研究期间，低剂量TAA给药的WT小鼠或无肝脏炎症的AID Tg小鼠均未在其肝组织中发生癌症。相比之下，所有TAA治疗的AID Tg小鼠在相同的观察期内均发生了多发性肉眼可见的肝细胞癌。全外显子组测序和额外的深度测序分析显示，在具有TAA介导的肝脏炎症的表达AIDS的肝脏中，各种基因中的体细胞突变的积累增加，包括双特异性磷酸酶6（Dusp 6），早期生长反应1（Egr 1）和DNA结合抑制剂2（Id 2），它们是推定的肿瘤抑制因子。微阵列和定量逆转录-聚合酶链反应分析显示，在肝脏炎症条件下，包括Dusp 6，Egr 1和Id 2在内的各种基因的转录上调。总之，这些发现表明炎症介导的靶基因（包括推定的肿瘤抑制基因）转录上调增加了发炎细胞获得体细胞突变的机会，并有助于加速发炎肝组织中的肿瘤发生。
Chronic inflammation triggers the aberrant expression of a DNA mutator enzyme, activation-induced cytidine deaminase (AID), and contributes to tumorigenesis through the accumulation of genetic aberrations. To gain further insight into the inflammation-mediated genotoxic events required for carcinogenesis, we examined the role of chronic inflammation in the emergence of genetic aberrations in the liver with constitutive AID expression. Treatment with thioacetamide (TAA) at low-dose concentrations caused minimal hepatic inflammation in both wild-type (WT) and AID transgenic (Tg) mice. None of the WT mice with low-dose TAA administration or AID Tg mice without hepatic inflammation developed cancers in their liver tissues over the 6 month study period. In contrast, all the AID Tg mice with TAA treatment developed multiple macroscopic hepatocellular carcinomas during the same observation period. Whole exome sequencing and additional deep-sequencing analyses revealed the enhanced accumulation of somatic mutations in various genes, including dual specificity phosphatase 6 (Dusp6), early growth response 1 (Egr1) and inhibitor of DNA binding 2 (Id2), which are putative tumor suppressors, in AID-expressing liver with TAA-mediated hepatic inflammation. Microarray and quantitative reverse transcription-polymerase chain reaction analyses showed the transcriptional upregulation of various genes including Dusp6, Egr1 and Id2 under hepatic inflammatory conditions. Together, these findings suggest that inflammation-mediated transcriptional upregulation of target genes, including putative tumor suppressor genes, enhances the opportunity for inflamed cells to acquire somatic mutations and contributes to the acceleration of tumorigenesis in the inflamed liver tissues.