title: 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.
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Jin
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Dan-Yan
authors.initials: DY
authors.lastname: Zhu
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Laboratory of Pathology and Pathologic Physiology, Department of Basic Medicine, College of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Mao
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Bo-Wen
authors.initials: BW
authors.lastname: Wu
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Zong-Fu
authors.initials: ZF
authors.lastname: Pan
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
authors.forename: Lan-Juan
authors.initials: LJ
authors.lastname: Li
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Xiang
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
authors.forename: Kun-Kai
authors.initials: KK
authors.lastname: Su
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yi-Jia
authors.initials: YJ
authors.lastname: Lou
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D014408:Biomarkers, Tumor / Q000378:metabolism; D054337:Cell Dedifferentiation / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D053539:Keratin-19 / Q000378:metabolism; D053552:Keratin-7 / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000187:drug effects; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D000418:Albumins; D034341:Aristolochic Acids; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D053539:Keratin-19; D053552:Keratin-7; C507496:Krt7 protein, mouse; C570876:Lin28b protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D000509:alpha-Fetoproteins; C577686:interleukin-6, mouse; C000228:aristolochic acid I
keywords: aristolochic acid I; c-Myc/Lin28B; paracrine IL-6; premalignant assessment; stem cell-derived liver-like tissue