Molecular Expression Analysis of β-Naphthoflavone-induced Hepatocellular Tumors in Rats

Abstract

The present study was performed to characterize molecular expression levels of preneoplastic and neoplastic lesions induced by b-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/EBPa). 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 realtime 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.

Selenium and selenocysteine: roles in cancer, health, and development

“…Furthermore, GPx2 contributes to the detoxification of carcinogens through its up-regulation by Nrf2/Keap1 [68], which also can be considered beneficial in terms of cancer prevention. However, this role of GPx2 may depend on the stage of cancer, as up-regulation of Nrf2-targets also has been described to provide hepatic cancer cells with an anti-oxidative advantage [92]. Additionally, since GPx2 is a target for the Wnt-pathway [93], which is associated with cell proliferation, and is up-regulated by β-catenin [94], it may also play a role in promoting tumor growth.…”

CONSTITUTIVE ANDROSTANE RECEPTOR DEPENDENT AND INDEPENDENT MODULATION OF CYP3A2, CYP1A2 BY PHENOBARBITAL AND FIBRATE IN RATS’ LIVER

“…It is known that the cytochrome P450 family generates ROS as byproducts of microsomal oxidation. It was stated that the production of ROS due to increased CYP1A expression is induced not only by classical AhR ligand but also the atypical non-AhR ligand (Dewa et al, 2009). Then it was recently speculated by Hayashi et al (2012) that most CYP1A inducers have ROS-mediated Science Publications AJBB liver tumor promoting activities in rats.…”

Epigenetic effects of natural polyphenols: A focus on SIRT1‐mediated mechanisms

“…Phloridzin, an apple polyphenol increased SOD and SIRT1 activities in Saccharomyces cerevisiae . Beta‐naphtoflavone increased the staining of HDAC1 in rats , whereas resveratrol, has been reported to stimulate the AMPK‐SIRT1 autophagy pathway in neurons .…”