title: Hepatic Premalignant Alterations Triggered by Human Nephrotoxin Aristolochic Acid I in Canines.
abstract: Aristolochic acid I (AAI) existing in plant drugs from Aristolochia species is an environmental human carcinogen associated with urothelial cancer. Although gene association network analysis demonstrated gene expression profile changes in the liver of human TP53 knock-in mice after acute AAI exposure, to date, whether AAI causes hepatic tumorigenesis is still not confirmed. Here, we show that hepatic premalignant alterations appeared in canines after a 10-day AAI oral administration (3 mg/kg/day). We observed c-Myc oncoprotein and oncofetal RNA-binding protein Lin28B overexpressions accompanied by cancer progenitor-like cell formation in the liver by AAI exposure. Meanwhile, we found that forkhead box O1 (FOXO1) was robustly phosphorylated, thereby shuttling into the cytoplasm of hepatocytes. Furthermore, utilizing microarray and qRT-PCR analysis, we confirmed that microRNA expression significantly dysregulated in the liver treated with AAI. Among them, we particularly focused on the members in let-7 miRNAs and miR-23a clusters, the downstream of c-Myc and IL6 receptor (IL6R) signaling pathway linking the premalignant alteration. Strikingly, when IL6 was added in vitro, IL6R/NF-κB signaling activation contributed to the increase of FOXO1 phosphorylation by the let-7b inhibitor. Therefore, it highlights the new insight into the interplay of the network in hepatic tumorigenesis by AAI exposure, and also suggests that anti-premalignant therapy may be crucial for preventing AAI-induced hepatocarcinogenesis.
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Ke
authors: K
authors: Jin
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, PR China. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China.
authors: Kun-kai
authors: KK
authors: Su
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Tong
authors: T
authors: Li
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Xia-qing
authors: XQ
authors: Zhu
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Qi
authors: Q
authors: Wang
authors: The Population Council at the Rockefeller University, New York, USA. Institute of Reproductive Biomedicine, the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, PR China.
authors: Ren-shan
authors: RS
authors: Ge
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Zong-fu
authors: ZF
authors: Pan
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Bo-wen
authors: BW
authors: Wu
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Li-jun
authors: LJ
authors: Ge
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Yi-han
authors: YH
authors: Zhang
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Yi-fan
authors: YF
authors: Wang
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Guo-fang
authors: GF
authors: Shen
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Dan-yan
authors: DY
authors: Zhu
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, PR China. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China.
authors: Chun-sheng
authors: CS
authors: Xiang
authors: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, PR China. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The 1st Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China. yijialou@zju.edu.cn ljli@zju.edu.cn.
authors: Lan-juan
authors: LJ
authors: Li
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China. yijialou@zju.edu.cn ljli@zju.edu.cn.
authors: Yi-jia
authors: YJ
authors: Lou
mesh_terms: D000284:Administration, Oral; D000818:Animals; D030022:Aristolochia / Q000737:chemistry; D034341:Aristolochic Acids / Q000008:administration & dosage / Q000633:toxicity*; D063646:Carcinogenesis / Q000187:drug effects* / Q000378:metabolism; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000008:administration & dosage / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D000071161:Forkhead Box Protein O1; D015850:Interleukin-6; D035683:MicroRNAs; D016328:NF-kappa B; D010936:Plant Extracts; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D019947:Receptors, Interleukin-6; C000228:aristolochic acid I