Aristolochic acids exposure was not the main cause of liver tumorigenesis in adulthood

Acta Pharmaceutica Sinica B

Tao Luo¹  Jiao Wang²  Lei Chen²  Lingyan Xu²  Qiqi Cao²  Xiaohe Xiao²  Yaping Dong²  Chunyu Wang³  Zhaofang Bai⁴  Huisi He⁵  Xiuwu Bian⁵  Zhichao Jin⁶  Wen Wen⁶  Jin Ren⁷  Guozhen Xing⁸  Shuzhen Chen⁹  Zhixuan Li⁹  Jia Ge⁹  Xinming Qi⁹  Yishan Zhong⁹  Hongyang Wang⁹  Zhecai Fan⁹ 

[1] Fudan University Shanghai Cancer Center, Shanghai 200032, China;International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China;Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China;The Graduate School of Fujian Medical University, Fuzhou 350122, China;Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China;Department of Health Statistics, Faculty of Medical Service, Second Military Medical University, Shanghai 200438, China;Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China;National Center for Liver Cancer, Second Military Medical University, Shanghai 200438, China;

关键词: Aristolochic acids (AAs);    Mutational signature;    AA–DNA adduct;    Hepatocellular carcinoma (HCC);    Liver tumorigenesis;    Hepatitis B virus (HBV);   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown