ToxSci Advance Access originally published online on January 24, 2006
Toxicological Sciences 2006 90(2):331-336; doi:10.1093/toxsci/kfj116
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Inhibition of Hepatocarcinogenesis by the Deletion of the p50 Subunit of NF-
B in Mice Administered the Peroxisome Proliferator Wy-14,643
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* Graduate Center for Nutritional Sciences, Graduate Center for Toxicology, Department of Microbiology, Immunology, and Molecular Genetics, and Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky 40506; and ¶ Uludag University, Faculty of Veterinary Medicine, Department of Food Hygiene and Technology, 16059, Gorukle kampusu, Bursa, Turkey
1 To whom correspondence should be addressed at University of Kentucky, Graduate Center for Nutritional Sciences, 222 Funkhouser Building, Lexington, KY 40506-0054. Fax: (859) 323-0061. E-mail: hglauert{at}uky.edu.
Received November 21, 2005; accepted January 20, 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Wy-14,643 (WY) is a hypolipidemic drug that induces hepatic peroxisome proliferation and tumors in rodents. We previously showed that peroxisome proliferators increase NF-
B DNA binding activity in rats, mice, and hepatoma cell lines, and that mice deficient in the p50 subunit of NF-B had much lower cell proliferation in response to the peroxisome proliferator ciprofibrate. In this study we examined the promotion of hepatocarcinogenesis by WY in the p50 knockout (–/–) mice. The p50 –/– and wild type mice were first administered diethylnitrosamine (DEN) as an initiating agent. Mice were then fed a control diet or a diet containing 0.05% WY for 38 weeks. Wild-type mice receiving DEN only developed a low incidence of tumors, and the majority of wild-type mice receiving both DEN and WY developed tumors. However, no tumors were seen in any of the p50 –/– mice. Cell proliferation and apoptosis were measured in hepatocytes by BrdU labeling and the TUNEL assay, respectively. Treatment with DEN + WY increased both cell proliferation and apoptosis in both the wild-type and p50 –/– mice; DEN treatment alone has no effect. In the DEN/WY-treated mice, cell proliferation and apoptosis were slightly lower in the p50 –/– mice than in the wild-type mice. These data demonstrate that NF-B is involved in the promotion of hepatic tumors by the peroxisome proliferator WY; however, the difference in tumor incidence could not be attributed to alterations in either cell proliferation or apoptosis.
Key Words: NF-B; peroxisome; carcinogenesis; cell proliferation; apoptosis.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Peroxisome proliferators are a group of chemically distinct compounds capable of eliciting a persistent peroxisome proliferation in hepatocytes and promoting liver tumors in rats and mice (Cattley et al., 1998
; Rao and Reddy, 1987). These chemicals activate the peroxisome proliferator-activated receptor-alpha (PPAR
), which leads to an increase in the size and number of peroxisomes as well as activating genes encoding several enzymes of the peroxisomal ß-oxidation pathway (Eacho and Feller, 1991; Schoonjans et al., 1996). The rate limiting enzyme of this pathway, fatty acyl CoA oxidase (FAO), produces hydrogen peroxide (H2O2) as a by-product. The activity of this enzyme is increased 10- to 15-fold by peroxisome proliferators such as ciprofibrate or Wy-14,643 (Rao and Reddy, 1987). In contrast, the activity of the H2O2-detoxifying enzyme catalase is only increased about two-fold by peroxisome proliferators (Rao and Reddy, 1987). It has been proposed that this imbalance in FAO and catalase induction may result in the accumulation of H2O2, which could at least partially be responsible for the effects of peroxisome proliferators. Several studies have found that the administration of peroxisome proliferators leads to lipid peroxidation and oxidative DNA damage, but other studies have not (O'Brien et al., 2005). Peroxisome proliferators have been found to decrease the levels of several cellular antioxidants and antioxidant enzymes, including vitamins C and E, and glutathione peroxidase (O'Brien et al., 2005).
In addition to these biochemical changes, peroxisome proliferators increase cell proliferation in the liver soon after they are administered (Reddy and Lalwani, 1983). Cell proliferation eventually returns to basal levels for many peroxisome proliferators, but remains elevated for others (Chen et al., 1994; Eacho et al., 1991; Marsman et al., 1988; Yeldandi et al., 1989). In addition to stimulating DNA synthesis, peroxisome proliferators have been shown to inhibit apoptosis in normal and preneoplastic hepatocytes (Bayly et al., 1993, 1994; Roberts et al., 1995; Schulte-Hermann et al., 1995). The withdrawal of peroxisome proliferators leads to rapid reduction in liver weight, presumably in part by apoptosis (Schulte-Hermann et al., 1995).
In spite of numerous studies, the link between peroxisome proliferators and hepatocarcinogenesis on a molecular and cellular level is not fully understood. In addition, the link between active oxygen production by peroxisome proliferator-induced enzymes and carcinogenesis has not been demonstrated. In several studies using rats and mice, we have shown that peroxisome proliferators increase the DNA binding activity of the transcription factor nuclear factor-B (NF-B) (Li et al., 1996; Nilakantan et al., 1998; Tharappel et al., 2001). NF-B is normally found in the cytoplasm as an inactive complex consisting primarily of two subunits (p50 and p65) which are bound to an inhibitory subunit, IB; upon activation, NF-B is released from IB and translocates to the nucleus, where it increases the transcription of specific genes (Verma et al., 1995). NF-B is important in the activation of genes that regulate cell proliferation and apoptosis in various cell types (Barkett and Gilmore, 1999; Beg et al., 1995; Demartin et al., 1999; Sha et al., 1995). Reactive oxygen species, including H2O2, are activators of NF-B, while the addition of antioxidants such as vitamin E can block activation of NF-B (Calfee-Mason et al., 2004; Gabbita et al., 2000; Li et al., 2000a,b; Meyer et al., 1994; Nilakantan et al., 1998). This has led us to hypothesize that peroxisome proliferators activate NF-B through the induction of H2O2-generating enzymes such as FAO or through the down-regulation of antioxidants and antioxidant enzymes, such as vitamin E and glutathione peroxidase. We subsequently found that NF-B can be activated by the overexpression of FAO in Cos cells, and that ciprofibrate-induced NF-B activation can be inhibited by vitamin E or N-acetyl cysteine in rat hepatoma cells, by dietary vitamin E in rats, and by catalase overexpression in mice (Calfee-Mason et al., 2004; Li et al., 2000a,b; Nilakantan et al., 1998). Catalase overexpression also inhibited ciprofibrate-induced cell proliferation in hepatocytes (Nilakantan et al., 1998).
In this study, we examined the hypothesis that NF-B activation is necessary for the promotion of hepatic tumors by peroxisome proliferators. We used a mouse model that is deficient in the p50 subunit of NF-B (Sha et al., 1995). We recently observed that the induction of cell proliferation by the peroxisome proliferator ciprofibrate was inhibited in p50 –/– mice (Tharappel et al., 2003). Wild-type and p50 –/– mice were injected with diethylnitrosamine (DEN) and then were administered the peroxisome proliferator Wy-14,643 (WY) for 38 weeks. The incidence of tumors, the rates of cell proliferation and apoptosis, and the activity of the peroxisome proliferator-induced enzyme fatty acyl CoA oxidase were then quantified.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Chemicals.
Wy-14,643 (WY) was purchased from Chem-Syn Synthesis (Lenexa, Kansas). Anti-bromodeoxyuridine (BrdU) antibody was purchased from Becton Dickinson (San Jose, CA); all other antibodies were purchased from Santa Cruz Biotech (Santa Cruz, CA). The Vectastain kit for immunostaining was obtained from Vector Laboratories (Burlingame, CA). The antigen retrieval solution Citra was purchased from BioGenex (San Ramon, CA). All other chemicals were purchased from Sigma Chemical Co. (St. Louis, MO).
Experimental design.
Mice homozygous for p50 –/– deletion and B6129SF2/J age-matched wild type controls were obtained from our breeding colony; founders had been obtained from The Jackson Laboratory (Bar Harbor, ME). After weaning, mice were fed an unrefined diet (Harlan Teklad 2018 Global 18% protein rodent diet) and water ad libitum. When the mice of both strains were eight weeks old, they received either an ip injection of DEN (90 mg/kg) or an equivalent amount of saline. Two weeks later, mice were fed either a diet containing 0.05% WY or a control diet for 38 weeks. Six days before euthanasia, mice were provided drinking water containing bromodeoxyuridine (BrdU, 0.5 mg/ml) (Ledda-Columbano et al., 1998). Mice were euthanized by overexposure to carbon dioxide and livers removed. A portion of the liver was fixed in formalin for histology and the remainder was frozen in liquid nitrogen and then stored at –80°C.
BrdU immunohistochemical staining.
The paraffin-embedded liver tissues were sectioned, stained with an anti-BrdU antibody, and counter-stained with hematoxylin. The staining was carried out using the Vectastain ABC Kit (Vector Laboratories, Burlingame, CA), according to the protocol provided by the manufacturer. Cells that had incorporated BrdU were easily identified as those with brown nuclei. At least 3000 hepatocellular nuclei per slide (1000 in each of three lobes) were counted in random fields and the labeling index was expressed as a percentage of the number of labeled hepatocyte nuclei out of total number of hepatocyte nuclei counted.
Apoptosis assay (TUNEL).
The terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) apoptosis assay kit was purchased from Intergen (Purchase, NY). The assay was performed on paraffin sections following the manufacturer's protocol. At least 3000 nuclei were randomly counted per slide and the apoptotic index was expressed as the percentage of number of labeled apoptotic bodies of the total number of nuclei counted.
Fatty Acyl CoA Oxidase (FAO) assay.
FAO activity in liver tissue homogenates was determined using lauroyl CoA as the substrate as described by Poosch and Yamazaki (1986).
Statistical analyses.
Tumor incidence data were analyzed by 
2 analyses. Body weight, liver weight, FAO, cell proliferation, and apoptosis data were analyzed by two-way analysis of variance (ANOVA). If a significant f value was observed, results were further analyzed using Bonferroni's test. The results are reported as means ± standard error of mean (SEM).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, we tested whether NF-
B is necessary for the promotion of DEN-initiated hepatic tumors by peroxisome proliferators. To accomplish this, we fed an unrefined diet containing 0.05% WY (or a control unrefined diet) to mice that were deficient in the p50 subunit of NF-B (p50 –/–; Sha et al., 1995) or to wild-type control mice. After 38 weeks of feeding, mice were euthanized; mice were given bromodeoxyuridine in their drinking water six days before euthanasia (Ledda-Columbano et al., 1998). Several mice died before the end of the study: one in the wild-type DEN group, two in the wild-type DEN/WY group, two in the p50 –/– DEN group, and two in the p50 –/– DEN/WY group. We examined whether wild-type or p50 –/– mice were responding to WY treatment by the increase in liver weights and the activity of hepatic fatty acyl CoA oxidase (FAO). The wild-type control mice or wild-type mice receiving only DEN weighed significantly more than wild-type mice fed WY or all p50 –/– mice (Table 1). Mice administered WY, both wild-type and p50 –/–, had higher liver weights and liver to body weight ratios than did mice not receiving WY (Table 1). The activity of FAO was higher in mice administered WY compared to those fed control diets (Fig. 1).
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The incidence of hepatic tumors is shown in Table 1. Only wild-type mice developed tumors; 25% of the wild-type mice administered DEN developed tumors, while 62.5% of wild-type mice receiving both DEN and WY developed tumors. The incidence of tumors in wild-type mice receiving both DEN and WY was significantly greater than in p50 –/– mice receiving both DEN and WY. All the tumors in this study were small and did not show certain histologic features that are known to be associated with hepatocellular carcinoma. Therefore, all the tumors in this study were classified as hepatocellular adenomas (Maronpot et al., 1986
).
Peroxisome proliferators in rodents lead to hepatomegaly, in part, by increasing cell proliferation (Chen et al., 1994; Eacho et al., 1991; Marsman et al., 1988; Reddy and Lalwani, 1983; Yeldandi et al., 1989). To examine the role of p50 in DNA synthesis, we quantified BrdU uptake, which serves as a measure of proliferation, by staining liver sections with anti-BrdU antibodies (Fig. 2). In both wild-type and p50 –/– mice, the labeling index was higher in mice treated with both DEN and WY than in control mice or mice treated with DEN only. There was no significant difference in the labeling index between the wild-type and p50 –/– mice in the ANOVA, and no significant interaction was observed. However, the labeling index in the p50 –/– mice administered both DEN and WY was about 40% lower than in wild-type mice adminstered both DEN and WY.
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Previous studies have shown that peroxisome proliferator treatment leads to a decrease in apoptosis in hepatocytes (Bayly et al., 1993
, 1994; Roberts et al., 1995; Schulte-Hermann et al., 1995). Apoptosis was evaluated in this study with the TUNEL assay (Fig. 3). In both wild-type and p50 –/– mice, the apoptotic index was higher in mice treated with both DEN and WY than in control mice or mice treated with DEN only. The apoptotic index was not significantly affected by the deletion of the p50 subunit in the ANOVA, and no significant interaction was observed. However, the apoptotic index in the p50 –/– mice administered both DEN and WY was about 60% lower than in wild-type mice adminstered both DEN and WY.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The data presented here indicate that NF-
B plays an important role in the induction of hepatic tumors by peroxisome proliferators. DEN induced a low incidence of tumors in the wild-type mice and further treatment with WY further increased the tumor incidence, but no tumors were seen in any of the p50 –/– mice. Treatment with WY increased both cell proliferation and apoptosis in both the wild-type and p50 –/– mice; therefore the difference in tumor incidence could not be attributed to alterations in either of these endpoints.
In the wild-type mice, treatment with DEN induced a low incidence of tumors. The long-term administration of WY following DEN treatment resulted in a high tumor incidence in the wild-type mice. This finding is in agreement with other studies showing that peroxisome proliferators have promoting activity in the liver (Borges et al., 1993; Cattley and Popp, 1989; Glauert et al., 1986; Reddy and Rao, 1978). No tumors were observed in any of the p50 –/– mice. Therefore the presence of intact NF-B appears to contribute to the promoting activities of peroxisome proliferators. This is the first in vivo study to show that deletion of an NF-B subunit results in the inhibition of tumorigenesis.
WY increased the rate of hepatocyte cell proliferation, which has been shown previously in several studies. However, no significant change was observed between wild-type and p50 –/– mice, although cell proliferation was 40% lower in the p50 –/– WY/DEN group than in the wild-type WY/DEN group. These findings contrast with earlier studies, which imply that NF-B is important in the induction of cell proliferation by peroxisome proliferators. Nilakantan et al. (1998) found that catalase overexpression decreased both the activation of NF-B and the induction of cell proliferation by ciprofibrate in mice. In studies comparing species that are responsive (rats) or non-responsive (hamsters) to peroxisome proliferator-induced carcinogenesis, NF-B was found to be activated by peroxisome proliferators in rats but not in hamsters, which correlated with the induction of cell proliferation in these two species (Durnford et al., 1998; Tharappel et al., 2001). In mice treated with the peroxisome proliferator ciprofibrate for 10 days, cell proliferation was increased in wild-type mice but inhibited in p50 –/– mice (Tharappel et al., 2003). In the present study, cell proliferation was only slightly inhibited in the p50 –/– mice administered both DEN and WY. However, the mice in the present study were treated with peroxisome proliferators for a much longer period of time than the animals in the above studies; it is likely that hepatocytes from p50 –/– in the present study have been able to overcome the previous inhibition, by a yet unknown mechanism.
In previous studies, peroxisome proliferators were shown to inhibit apoptosis in hepatocytes (Lu et al., 2004; Schulte-Hermann et al., 1995; Tharappel et al., 2003). NF-B has been found to have anti-apoptotic activity in several cell types, including hepatic cell lines, by several agents, including TNF- and TGF-ß (Barkett and Gilmore, 1999). The deletion of the p50 subunit was found to result in increased apoptosis in hepatocytes (Lu et al., 2004; Tharappel et al., 2003). In the present study, however, apoptosis was not significantly affected in p50 –/– mice compared to wild-type mice (although apoptosis was lower in p50 –/– mice receiving both DEN and WY compared to wild-type mice receiving the same treatment), and apoptosis was increased by WY administration. The mechanism for the differences with previous studies is not clear. As with cell proliferation, it is likely that long-term treatment or the age of the animals may be affecting the results. Also, a different peroxisome proliferator was used in the present study (WY) than in our previous studies.
Several studies have used genetically modified mice to examine the role of NF-B subunits on cell proliferation and apoptosis in the liver and other tissues. A clear role for NF-B in inhibiting apoptosis by TNF- or other apoptosis inducers in several cell types, including hepatocytes, has been demonstrated in studies in which NF-B activity has been inhibited by the deletion of one of its subunits, the inhibition of its translocation, or the expression of a dominant negative form of IB (Beg and Baltimore, 1996; Schoemaker et al., 2002; Vanantwerp et al., 1996; Wang et al., 1996; Xu et al., 1998). However, DNA synthesis and liver regeneration following partial hepatectomy or carbon tetrachloride treatment were not affected by the absence of the p50 subunit. In this latter study, increased levels of the p65 subunit may have compensated for the lack of p50 (Deangelis et al., 2001). Similarly, the hepatic-specific expression of a truncated IB super-repressor did not affect DNA synthesis, apoptosis, or liver regeneration following partial hepatectomy, but led to increased apoptosis after treatment with TNF- (Chaisson et al., 2002). Also, the hepatic inflammatory response after ischemia/reperfusion was not altered in p50 –/– mice (Kato et al., 2002). In the RALA 255–10G rat hepatocyte cell line, expression of an IB super-repressor inhibited cell proliferation but not apoptosis by TNF- (Xu et al., 1998). In addition, B cells lacking p50, RelB, or c-Rel (but not p52 or p65) have decreased proliferation in response to LPS (Horwitz et al., 1999; Kontgen et al., 1995; Sha et al., 1995; Snapper et al., 1996a,b). Overall, whether specific NF-B subunits are essential for cell proliferation depends on the tissue and the stimulus for DNA synthesis.
This study shows that the p50 subunit of the NF-B family is necessary for the promotion of hepatocarcinogenesis by peroxisome proliferators. To our knowledge, this represents the first study to show that deletion of an NF-B subunit results in the inhibition of tumorigenesis in vivo. The molecular mechanisms responsible for these changes, however, are not clear at this time. We found that Wy-14,643 increased both cell proliferation and apoptosis, but the changes observed did not correlate with the effects on tumor induction. This suggests that NF-B target genes that regulate proliferation and apoptosis are not responsible for the inhibition of tumorigenesis. Future studies will be needed to determine which NF-B-regulated genes are responsible for alterations in carcinogenesis that are induced or promoted by peroxisome proliferators.
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ACKNOWLEDGMENTS |
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This study was supported by National Cancer Institute grant CA74147, National Institute of Environmental Health Sciences grant ES11526, and the Kentucky Agricultural Experiment Station.
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