Premalignant alteration assessment in liver-like tissue derived from embryonic stem cells by aristolochic acid I exposure
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Tong Li1, Ke Jin1, Dan-yan Zhu1, Lu Li1, Zheng-rong Mao2, Bo-wen Wu1, Yi-fan Wang1, Zong-fu Pan1, Lan-juan Li3,4, Chun-sheng Xiang3,4, Kun-kai Su3,4, Yi-jia Lou1
1Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2Laboratory of Pathology and Pathologic Physiology, Department of Basic Medicine, College of Medicine, Zhejiang University, Hangzhou 310058, China
3State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
4Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
Yi-jia Lou, email: email@example.com
Kun-kai Su, email: firstname.lastname@example.org
Keywords: premalignant assessment, stem cell-derived liver-like tissue, paracrine IL-6, c-Myc/Lin28B, aristolochic acid I
Received: May 20, 2016 Accepted: September 20, 2016 Published: October 4, 2016
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.
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