Journal
ACTA PHARMACEUTICA SINICA B
Volume 12, Issue 5, Pages 2252-2267Publisher
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.11.0112211-3835
Keywords
Aristolochic acids (AAs); Mutational signature; AA-DNA adduct; Hepatocellular carcinoma (HCC); Liver tumorigenesis; Hepatitis B virus (HBV); Risk factors; Tumor prevention
Categories
Funding
- Shanghai Key Laboratory of Hepatobiliary Tumor Biology
- National Major Scientific and Technological Special Project for Significant New Drugs Development (China) [2018ZX09101002, 2018ZX09101002-001-001, 2018ZX09101002-001-002]
- National Natural Science Foundation of China [81830054, 91859205, 81988101, 81722034, 81802878]
- Shanghai Pujiang Program (China) [2019PJD059]
- Shanghai Sailing Program (China) [18YF1400200]
- Key Discipline Project of Shanghai Municipal Education Commission (China) [201901070007E00065]
- Ministry of Education Key Laboratory on Signaling Regulation and Military Key Laboratory and Targeting Therapy of Liver Cancer, Second Military Medical University, Shanghai, China
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This study investigated whether Aristolochic acids (AAs) were the main cause of liver cancer in the context of HBV infection in mainland China. The results showed that long-term administration of AAs barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role in infant mice. Furthermore, AAI induced dose-dependent accumulation of AA-DNA adduct in target organs in adult mice, with the most detected in the kidney instead of the liver. Overall, the data suggest that AA exposure is not a major threat of liver cancer in adulthood.
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. ?? 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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