title: 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) promotes mouse hepatocarcinogenesis by activating transforming growth factor-β and Wnt/β-catenin signaling pathways.
abstract: The purposes of the present study were to investigate the modifying effects of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a genotoxic carcinogen produced during cooking of protein-rich foods, and elucidate underlying mechanisms in a two-stage hepatocarcinogenesis mice model. Six-week-old B6C3F1 mice were subjected to two-thirds partial hepatectomy at the beginning of the study, followed by an intraperitoneal injection of diethylnitrosamine on day 1. Starting 1 week later, they were fed diets containing IQ at doses of 30, 100, or 300 ppm for 39 weeks. A dose-dependent trend for increase in eosinophilic altered foci as well as eosinophilic hepatocellular adenomas was observed, along with significant elevation in the incidence of hepatocellular carcinomas in the 100- and 300-ppm IQ groups as compared with initiation control group. Furthermore, IQ elevated the protein expression levels of Wnt1, transforming growth factor-β (TGF-β), TGF-β receptors 1 and 2 (TβR1 and TβR2), and phosphorylated c-Jun (p-c-Jun), while suppressing those of E-cadherin and p21(WAF1/Cip1). Moreover, translocation of β-catenin to the nuclei as well as upregulated nuclear expression of c-Myc and cyclin D1, which are downstream targets of β-catenin and p-c-Jun, were detected at 100 and 300 ppm. These findings suggest that IQ exerts dose-dependent promoting effects on mice hepatocarcinogenesis by activating TGF-β and Wnt/β-catenin signaling pathways and inhibiting cell adhesion.
authors.affiliation: Department of Pathology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Xie
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Anna
authors.initials: A
authors.lastname: Kakehashi
authors.forename: Shotaro
authors.initials: S
authors.lastname: Yamano
authors.forename: Masaki
authors.initials: M
authors.lastname: Tajiri
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004052:Diethylnitrosamine; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D006498:Hepatectomy; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011804:Quinolines / Q000633:toxicity*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D011804:Quinolines; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D004052:Diethylnitrosamine