Aristolochic acids exposure was not the main cause of liver tumorigenesis in adulthood.
Aristolochic acids exposure was not the main cause of liver tumorigenesis in adulthood.
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马兜铃酸暴露不是成年期肝脏肿瘤发生的主要原因
DOI：
10.1016/j.apsb.2021.11.011
复制
发表时间：
2022-05
影响因子：
14.5
通讯作者：
Wang, Hongyang
中科院分区：
文献类型：
--
作者：
Chen, Shuzhen;Dong, Yaping;Qi, Xinming;Cao, Qiqi;Luo, Tao;Bai, Zhaofang;He, Huisi;Fan, Zhecai;Xu, Lingyan;Xing, Guozhen;Wang, Chunyu;Jin, Zhichao;Li, Zhixuan;Chen, Lei;Zhong, Yishan;Wang, Jiao;Ge, Jia;Xiao, Xiaohe;Bian, Xiuwu;Wen, Wen;Ren, Jin;Wang, Hongyang
关键词：
马兜铃酸（AAs）因其肾毒性长期以来被认为是一种强效致癌物。马兜铃酸I（AAI）与DNA反应形成马兜铃内酰胺（AL）-DNA加合物，导致随后的A至T颠换突变，通常称为AA突变标签。以前的研究推断，AA在整个亚洲广泛涉及肝癌。在这项研究中，我们探讨是否AAs暴露是肝癌的主要原因，在中国大陆的背景下，HBV感染。从3个医学中心随机抽取1256例肝癌标本，采用改良的生物分析方法检测AAI-DNA加合物。AAI阳性检出率为5.10%。全基因组测序结果显示，107例肝癌患者中有8.41%的患者出现AA突变，表明AAI暴露率相对较低。在动物模型中，长期给予AAI几乎没有增加成年小鼠的肝脏肿瘤发生，与其在幼年小鼠中的肿瘤诱导作用相反。此外，AAI在成年小鼠的靶器官中诱导AA-DNA加合物的剂量依赖性蓄积，在肾脏而不是肝脏中检测到最多。总之，我们的数据表明，AA暴露不是成年期肝癌的主要威胁。
Aristolochic acids (AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I (AAI) reacts with DNA to form covalent aristolactam (AL)–DNA adducts, leading to subsequent A to T transversion mutation, commonly referred as AA mutational signature. Previous research inferred that AAs were widely implicated in liver cancer throughout Asia. In this study, we explored whether AAs exposure was the main cause of liver cancer in the context of HBV infection in mainland China. Totally 1256 liver cancer samples were randomly retrieved from 3 medical centers and a refined bioanalytical method was used to detect AAI–DNA adducts. 5.10% of these samples could be identified as AAI positive exposure. Whole genome sequencing suggested 8.41% of 107 liver cancer patients exhibited the dominant AA mutational signature, indicating a relatively low overall AAI exposure rate. In animal models, long-term administration of AAI barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role when subjected to infant mice. Furthermore, AAI induced dose-dependent accumulation of AA–DNA adduct in target organs in adult mice, with the most detected in kidney instead of liver. Taken together, our data indicate that AA exposure was not the major threat of liver cancer in adulthood.
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