Premalignant alteration assessment in liver-like tissue derived from embryonic stem cells by aristolochic acid I exposure

Abstract

The in vitro predictive evaluation of chemical carcinogenicity based on hepatic premalignance has so far not been established. Here, we report a novel approach to investigate the premalignant events triggered by human carcinogen aristolochic acid I (AAI) in the liver-like tissue derived from mouse embryonic stem cells. By AAI exposure, the liver-like tissue exhibited the paracrine interleukin-6 phenotypic characteristics. Hepatocytes expressed STAT3/p-STAT3, c-Myc and Lin28B in parallel. Some of them displayed the dedifferentiation characteristics, such as full of α-fetoprotein granules, increase in size, and nucleocytoplasmic shuttle of Oct4. When these cells were injected into mice, the xenografts mostly displayed the uniform area of hepatic-like tissue with malignant nuclei. The hepatic malignant markers, α-fetoprotein, cytokeratin 7 and cytokeratin 19, were co-expressed in albumin-positive areas, respectively. In conclusion, we established an approach to predict the hepatic premalignance triggered by carcinogen AAI. This premalignant assay system might aid to evaluate the effects of potential carcinogens in liver, and probably to screen the protecting against hepatocarcinogenic efficacy of pharmaceuticals in vitro.

Recognition of the toxicity of aristolochic acid

“…However, rats injected with AA and 1% orotic acid (for pH regulation) at a dose of 10 mg/kg/d for 10 weeks displayed glutathione‐S‐transferase 7‐7‐positive hepatic foci and nodules, which promoted the carcinogenic process in the livers . Li T concluded that both c‐Myc and Lin28B could be considered markers of carcinogenesis in liver‐like tissue due to AA I exposure . None of these experiments indicate that AA‐induced liver injury is caused by A‐T‐specific mutations.…”

DNA Adducts Formed by Aristolochic Acid Are Unique Biomarkers of Exposure and Explain the Initiation Phase of Upper Urothelial Cancer

“…Only a few years after the first description of AAN, UCC developed in almost 50% of these patients [ 27 , 36 , 37 ]. Recent studies indicated linking AA not only to upper urothelial cancers, but also renal cell carcinoma (RCC) [ 31 ] and to liver premalignant alterations [ 38 , 39 ].…”

Innovation for hepatotoxicity in vitro research models: A review

“…No studies using ESCs have successfully derived HLCs with adequate CYP activity in response to known reference compounds. It is clear that ESCs/HLCs are not currently sufficiently mature to emulate adult human PHs, and these cells are probably closer to fetal hepatocytes in phenotype (Goldring et al, ; Kia et al, ; Li et al, ).…”