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

Shuzhen Chen; Yaping Dong; Xinming Qi; Qiqi Cao; Tao Luo; Zhaofang Bai; Huisi He; Zhecai Fan; Lingyan Xu; Guozhen Xing; Chunyu Wang; Zhichao Jin; Zhixuan Li; Lei Chen; Yishan Zhong; Jiao Wang; Jia Ge; Xiaohe Xiao; Xiuwu Bian; Wen Wen; Jin Ren; Hongyang Wang

doi:10.1016/j.apsb.2021.11.011

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

Acta Pharm Sin B. 2022 May;12(5):2252-2267. doi: 10.1016/j.apsb.2021.11.011. Epub 2021 Nov 16.

Authors

Shuzhen Chen^{1

2}, Yaping Dong^{1

2

3

4}, Xinming Qi⁵, Qiqi Cao^{1

2}, Tao Luo^{6

7}, Zhaofang Bai⁸, Huisi He^{1

2}, Zhecai Fan^{1

2}, Lingyan Xu^{1

2}, Guozhen Xing⁵, Chunyu Wang⁸, Zhichao Jin⁹, Zhixuan Li^{1

2}, Lei Chen^{1

2}, Yishan Zhong¹, Jiao Wang^{6

7}, Jia Ge^{6

7}, Xiaohe Xiao⁸, Xiuwu Bian^{6

7}, Wen Wen^{1

2}, Jin Ren⁵, Hongyang Wang^{1

2

3

4}

Affiliations

¹ National Center for Liver Cancer, Second Military Medical University, Shanghai 200438, China.
² International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
³ Fudan University Shanghai Cancer Center, Shanghai 200032, China.
⁴ The Graduate School of Fujian Medical University, Fuzhou 350122, China.
⁵ 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.
⁶ Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
⁷ Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
⁸ China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China.
⁹ Department of Health Statistics, Faculty of Medical Service, Second Military Medical University, Shanghai 200438, China.

Abstract

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.

Keywords: AAI, Aristolochic acid I; AAs, aristolochic acids; AA–DNA adduct; AFP, alpha fetoprotein; AL, aristolactam; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Aristolochic acids (AAs); CHERRY, Chinese Electronic Health Records Research; COSMIC, Catalogue of Somatic Mutations in Cancer; CRE, creatinine; DEN, N-nitrosodiethylamine; EHBH, Eastern Hepatobiliary Surgery Hospital; FFPE, formalin-fixed paraffin-embedded; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; Hepatitis B virus (HBV); Hepatocellular carcinoma (HCC); Liver tumorigenesis; MVI, microvessel invasion; Mutational signature; Risk factors; SNV, somatic single nucleotide variant; TCGA, The Cancer Genome Atlas; Tumor prevention; WGS, whole genome sequencing; WT, wild type; dA-ALI, 7-deoxyadenosin-N6-yl aristolactam I.