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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies [1, 2]
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
We demonstrated the IL-6 paracrine and c-Myc oncogenic transcription factor (Myc)/Lin28B/AFP expression in the mouse embryonic stem (ES) cell-derived liver-like tissue by AAI exposure
Summary
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies [1, 2]. Premalignant alterations are believed to take a pivotal role in the pathological processes of HCC [2,3,4]. Mouse embryonic stem (ES) cell-derived liver-like tissue could be an option for an in vitro paracrine IL-6-producing model. Our and others studies revealed that the liver-like tissue possesses the 5-lipoxygenase pathway, metabolic functions of cytochrome P450 family and phase II metabolic enzymes at the terminal differentiation stage [8,9,10,11]. It has been becoming an in vitro hepatic pathophysiological and drug metabolism model. ES cell-derived hepatocytes have been used to evaluate the carcinogenic hazard of chemicals using Affymetrix gene microarray measurements based on applying an ANOVA model [5]. Pure hepatocytes do not possess the tissue function, and hardly show the ascendancy described above
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