Journal Article

2-Amino-3-Methylimidazo[4,5<i>-f</i>]Quinoline (IQ) Promotes Mouse Hepatocarcinogenesis by Activating Transforming Growth Factor-β and Wnt/β-Catenin Signaling Pathways

Xiao-Li Xie, Min Wei, Anna Kakehashi, Shotaro Yamano, Masaki Tajiri and Hideki Wanibuchi

in Toxicological Sciences

Volume 125, issue 2, pages 392-400
Published in print February 2012 | ISSN: 1096-6080
Published online November 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr314
2-Amino-3-Methylimidazo[4,5-f]Quinoline (IQ) Promotes Mouse Hepatocarcinogenesis by Activating Transforming Growth Factor-β and Wnt/β-Catenin Signaling Pathways

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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 p21WAF1/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.

Keywords: IQ; hepatocarcinogenesis; TGF-β pathway; Wnt/β-catenin pathway; E-cadherin

Journal Article.  5433 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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