The Mutational Features of Aristolochic Acid-Induced Mouse and Human Liver Cancers
The Mutational Features of Aristolochic Acid-Induced Mouse and Human Liver Cancers
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马兜铃酸诱导小鼠和人类肝癌的突变特征
DOI：
10.1002/hep.30863
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发表时间：
2019-11-06
期刊：
影响因子：
13.5
通讯作者：
Han, Ze-Guang
中科院分区：
文献类型：
--
作者：
Lu, Zhao-Ning;Luo, Qing;Han, Ze-Guang
背景和目的马兜铃酸（AA）暴露与人类肝癌有统计学相关性。然而，没有直接的证据表明AA是诱发肝癌的。本研究旨在基于小鼠模型建立AA暴露与肝癌之间的直接因果关系，然后探索AA介导的基因组改变，这些基因组改变可能与AA相关突变特征的人类癌症有关。方法和结果我们进行小鼠，包括磷酸酶和张力蛋白同源物（Pten）缺陷的，马兜铃酸I（AAI）单独或AAI和四氯化碳的组合。值得注意的是，AAI暴露以剂量依赖性方式诱导小鼠肝癌，包括肝细胞癌（HCC）和HCC与肝内胆管细胞癌的组合。此外，AAI暴露也增强了这些CCl 4处理或Pten缺陷小鼠的肿瘤发生。AAI导致DNA损伤和AAI-DNA加合物，可通过特征性腺嘌呤-胸腺嘧啶颠换引发肝癌，如全面的基因组分析所示，其揭示了Harvey大鼠肉瘤病毒癌基因的复发性突变。有趣的是，AA相关的突变特征主要与人类肝癌有关，特别是来自中国的人。此外，我们检测到25.8%（16/62）的癌旁肝组织中的AAI-DNA加合物从随机选择的中国肝癌患者。此外，基于系统发育分析，在AA相关的小鼠和人肝癌的起始恶性克隆中发现了特征性突变，其中肿瘤蛋白p53和Janus激酶1的突变倾向于在AA影响的人肿瘤中显著富集。结论本研究为AA诱发肝癌的恶性克隆进化过程中的特征性突变过程提供了证据，为AA相关人类肿瘤尤其是肝癌的预防和诊断奠定了坚实的基础。
Background and Aims Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure-induced liver cancer is absent. This study aims to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA-mediated genomic alterations that could be implicated in human cancers with AA-associated mutational signature. Approach and Results We subjected mice, including phosphatase and tensin homolog (Pten)-deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl4. Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose-dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl4-treated or Pten-deficient mice. AAI led to DNA damage and AAI-DNA adduct that could initiate liver cancers through characteristic adenine-to-thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA-associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI-DNA adduct in 25.8% (16/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA-implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA-affected human tumors. Conclusions This study provides evidence for AA-induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA-associated human cancers, especially liver cancers.