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[Display omitted] • Aristolochic acid I promotes the motility of HCC cells. • EMT is involved in aristolochic acid I-induced cell motility. • Aristolochic acid I activates the C3a/C3aR system in HCC cells. • The C3a/C3aR system plays a role in aristolochic acid I-induced HCC cell motility. Aristolochic acid is an established human carcinogen. Previous reports have demonstrated a link between aristolochic acid exposure and liver cancer prevalence in Asia. The C3a/C3AR axis plays an essential role in regulating cancer cell migration and invasion. Here, we focused on the relationship between AA I-induced migration, invasion and epithelial-mesenchymal transition in HCC cells, as well as the possible role of the C3a/C3AR axis in these effects. HCC cells were exposed to different concentrations of AA I for 24 h. Cell migration and invasion abilities were evaluated with wound healing assays and Transwell invasion assays. The protein and mRNA expression levels were detected by western blot, immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR) assays. Furthermore, the level of complement component C3a in the cell supernatant was determined by enzyme-linked immunosorbent assay. C3aRA, a C3a receptor antagonist, was used to block the C3a-C3aR axis. The results showed that aristolochic acid I promoted HCC cell invasion and migration. AAI exposure also induced EMT in HCC cells through E-cadherin downregulation and Snail, N-cadherin, and vimentin upregulation. AAI exposure increased the levels of secreted C3a and the expression of C3aR protein and mRNA in HCC cells. We further found that AA I-induced C3a/C3AR activation was involved in these effects. AA I-induced epithelial-to-mesenchymal transition (EMT), cell migration, and invasion were decreased by C3aR inhibition. Overall, our results suggest that AA I induces HCC cell migration and invasion through the EMT process, which is regulated by C3a/C3aR axis activation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aristolochic acid (AA-I) induces upper urothelial tract cancer (UUTC) and bladder cancer (BC) in humans. AA-I forms the 7-(2ʹ-deoxyadenosin-N6-yl)aristolactam I (dA-AL-I) adduct, which induces multiple A:T-to-T:A transversion mutations in TP53 of AA-I exposed UTUC patients. This mutation is rarely reported in TP53 of other transitional cell carcinomas and thus recognized as an AA-I mutational signature. A:T-to-T:A transversion mutations were recently detected in bladder tumors of patients in Asia with known AA-I-exposure, implying that AA-I contributes to BC. Mechanistic studies on AA-I genotoxicity have not been reported in human bladder. In this study, we examined AA-I DNA adduct formation and mechanisms of toxicity in the human RT4 bladder cell line. The biological potencies of AA-I were compared to 4-aminobiphenyl, a recognized human bladder carcinogen, and several structurally related carcinogenic heterocyclic aromatic amines (HAA), which are present in urine of smokers and omnivores. AA-I (0.05–10 µM) induced a concentration- and time-dependent cytotoxicity. AA-I (100 nM) DNA adduct formation occurred at over a thousand higher levels than the principal DNA adducts formed with 4-ABP or HAAs (1 µM). dA-AL-I adduct formation was detected down to a 1 nM concentration. Studies with selective chemical inhibitors provided evidence that NQO1 is the major enzyme involved in AA-I bio-activation in RT4 cells, whereas CYP1A1, another enzyme implicated in AA-I toxicity, had a lesser role in bio-activation or detoxification of AA-I. AA-I DNA damage also induced genotoxic stress leading to p53-dependent apoptosis. These biochemical data support the human mutation data and a role for AA-I in BC. [ABSTRACT FROM AUTHOR]

The authors argue that the toxicity of botanical medicines is an overlooked international public health problem as of 2016, and it mentions how herbal remedies are commonly used in places where access to health care is limited and traditional healing cultures exist. Aristolochic acids are examined in relation to renal failure and interstitial tubulonephritis. Cancer and other health problems in Taiwan and China are assessed, along with the U.S. Food and Drug Administration.