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Molecular Expression Analysis of β-Naphthoflavone-induced Hepatocellular Tumors in Rats
1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan Correspondence: Kunitoshi Mitsumori, Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; e-mail:mitsumor{at}cc.tuat.ac.jp.
The present study was performed to characterize molecular expression levels of preneoplastic and neoplastic lesions induced by β-naphthoflavone (BNF), an aryl hydrocarbon receptor (AhR) agonist in rat hepatocarcinogenesis. Male F344 rats were initiated with an intraperitoneal injection of 200 mg/kg N-diethylnitrosamine, and two weeks later, they were fed a diet containing 0% or 1% BNF for twenty-eight weeks. All animals were subjected to a two-thirds partial hepatectomy at week 3 and sacrificed at week 30. Histopathologically, BNF increased the incidence and multiplicity of altered foci (1.7-fold and 3.3-fold) and hepatocellular adenomas (HCAs) (4.0-fold and 4.7-fold). Immunohistochemically, BNF increased the number of proliferating cell nuclear antigen (PCNA)-positive cells in altered foci (2.3-fold) and HCAs (6.7-fold) compared with the surrounding tissue and decreased the staining of cell cycle regulators (P21, C/EBP
Key Words: β-naphthoflavone • hepatocarcinogenesis • tumor promotion • oxidative stress • cell proliferation • histone deacetylase • rat Abbreviations: Afar, aldo-keto reductase family 7, member A3 (aflatoxin aldehyde reductase, Akr7a3); • AhR, aryl hydrocarbon receptor; • AKR7, aldo-keto reductase family 7; • BNF, β-naphthoflavone; • C/EBP
This version was published on June
1, 2009 Toxicologic Pathology, Vol. 37, No. 4,
446-455 (2009) |
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). In addition, loss of reactivity for AhR-regulated (CYP1A1, CYP1B1) molecules and increased reactivity of Nrf-2-regulated (AKR7, GPX2) molecules were also observed in proliferative lesions. Furthermore, increased staining of histone deacetylase (HDAC1) in the nucleus was prominent in HCAs. The differential expression patterns were confirmed at mRNA levels by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. These results suggest that enhanced cell proliferation and protection against oxidative stress play an important role in BNF-induced hepatocarcinogenesis in rats.