Altered Gene Expression in Rat Colonic Adenocarcinomas Induced in an Azoxymethane plus 2-Amino-1-Methyl-6-Phenylimidazo[4,5-&lt;i&gt;b&lt;/i&gt;]- Pyridine Initiation-Promotion Model

Doi, Kenichiro; Hagihara, Atsushi; Wei, Min; Yunoki, Takayuki; Fukushima, Shoji; Wanibuchi, Hideki

doi:10.1159/000127423

Cited by 5 publications

(3 citation statements)

References 57 publications

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“…For example, increased Stat1 expression was associated with the Mthfd1 gt/þ genotype by microarray analysis. Increased Stat1 expression has been shown to increase tumor development in AOM-treated rats (39); however, Stat1 expression is not required for polyp development in Apc min/þ mice (40). Furthermore, many of the candidate genes contained putative CpG islands indicating the potential for methylation-regulated expression.…”

Section: Discussionmentioning

confidence: 99%

Mthfd1 is a modifier of chemically induced intestinal carcinogenesis

MacFarlane

Perry²,

McEntee³

et al. 2010

Carcinogenesis

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The causal metabolic pathways underlying associations between folate and risk for colorectal cancer (CRC) have yet to be established. Folate-mediated one-carbon metabolism is required for the de novo synthesis of purines, thymidylate and methionine. Methionine is converted to S-adenosylmethionine (AdoMet), the major one-carbon donor for cellular methylation reactions. Impairments in folate metabolism can modify DNA synthesis, genomic stability and gene expression, characteristics associated with tumorigenesis. The Mthfd1 gene product, C1-tetrahydrofolate synthase, is a trifunctional enzyme that generates one-carbon substituted tetrahydrofolate cofactors for one-carbon metabolism. In this study, we use Mthfd1(gt/+) mice, which demonstrate a 50% reduction in C1-tetrahydrofolate synthase, to determine its influence on tumor development in two mouse models of intestinal cancer, crosses between Mthfd1(gt/+) and Apc(min)(/+) mice and azoxymethane (AOM)-induced colon cancer in Mthfd1(gt/+) mice. Mthfd1 hemizygosity did not affect colon tumor incidence, number or load in Apc(min/+) mice. However, Mthfd1 deficiency increased tumor incidence 2.5-fold, tumor number 3.5-fold and tumor load 2-fold in AOM-treated mice. DNA uracil content in the colon was lower in Mthfd1(gt/+) mice, indicating that thymidylate biosynthesis capacity does not play a significant role in AOM-induced colon tumorigenesis. Mthfd1 deficiency-modified cellular methylation potential, as indicated by the AdoMet: S-adenosylhomocysteine ratio and gene expression profiles, suggesting that changes in the transcriptome and/or decreased de novo purine biosynthesis and associated mutability cause cellular transformation in the AOM CRC model. This study emphasizes the impact and complexity of gene-nutrient interactions with respect to the relationships among folate metabolism and colon cancer initiation and progression.

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Section: Discussionmentioning

confidence: 99%

Mthfd1 is a modifier of chemically induced intestinal carcinogenesis

MacFarlane

Perry²,

McEntee³

et al. 2010

Carcinogenesis

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“…Since HCAs may contribute to human colon cancer development, this latter model may be useful for inducing colon carci-nogenesis in animal model systems and to investigate the chemopreventive activity of potential agents against colon carcinogenesis. Recently, Doi et al (99) identified a set of PhIP-altered genes (e.g. Stat1 and VEGF) in rat colon tumors by giving an initiating dose of AOM followed by varying doses of PhIP (up to 200 p.p.m.…”

Section: Hcasmentioning

confidence: 99%

Mouse models for the study of colon carcinogenesis

2008

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The study of experimental colon carcinogenesis in rodents has a long history, dating back almost 80 years. There are many advantages to studying the pathogenesis of carcinogen-induced colon cancer in mouse models, including rapid and reproducible tumor induction and the recapitulation of the adenoma-carcinoma sequence that occurs in humans. The availability of recombinant inbred mouse panels and the existence of transgenic, knock-out and knock-in genetic models further increase the value of these studies. In this review, we discuss the general mechanisms of tumor initiation elicited by commonly used chemical carcinogens and how genetic background influences the extent of disease. We will also describe the general features of lesions formed in response to carcinogen treatment, including the underlying molecular aberrations and how these changes may relate to the pathogenesis of human colorectal cancer.

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“…PhIP was shown to be metabolized by CYP1A2 [29], and to exert carcinogenicity in the rat colon [30].Furthermore, recent data indicated that PhIP could cause stomach injury, oxidative stress in rat stomach as well as the activation of c-fos and c-jun and inactivation of p16, which may play a role in the pathogenesis of PhIP-associated stomach cancer [31]. Moreover, PhIP induced signal transducer and activator of transcription 1 (Stat1) and vascular endothelial growth factor (VEGF) expression which was suggested to be involved in PhIP-enhanced colon tumorigenesis in the post-initiation phase [32] (Table 1) (Figure 3). Furthermore, recent studies reported that down-regulation of breast cancer resistance protein (BCRP) expression in murine colon adenomas leads to an accumulation of PhIP in the above-mentioned lesions [33], thus suggesting that BCRP is an important PhIP efflux transporter.…”

Section: Carcinogenicity Of 2-amino-1-methyl-6-phenylimidazo[45b] Pymentioning

confidence: 99%

Threshold in Carcinogenicity of Genotoxic Carcinogens

Kakehashi

Fukushima²,

Wei³

et al. 2014

J Carcinog Mutagen

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Nowadays the idea of threshold in the carcinogenicity of chemical carcinogens has attracted interest in the field of carcinogenesis. With genotoxic agents there is considerable experimental evidence in support of the idea. Here, we report on the low dose carcinogenicity in rats observed with heterocyclic amines contained in cooked food, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP), and contaminants of natural and manufactured food products, N-nitrosocompounds such as N-nitrosodiethylamine (DEN) and N-nitrosodimethylamine (DMN). The existence of a no-effect level for MeIQx carcinogenicity was confirmed in a medium-term rat liver bioassay. Treatment with increasing doses of MeIQx caused sequence of events to occur in the liver tissue: first, the induction of DNA-MeIQx adducts at low doses, then an increase of DNA 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation and lacI gene mutations, following by the development of preneoplastic lesions, glutathione S-transferase placental form positive (GST-P +) foci, at high doses. In another study, IQ was found to induce preneoplastic lesions in the rat liver at high doses, but lack any effect at low doses. Similarly, examination of carcinogenicity of a well-known colon genotoxic carcinogen PhIP have shown that application at low doses caused the formation of PhIP-DNA adducts, however, a surrogate marker of preneoplastic lesions in the colon, aberrant crypt foci, were detected only at high doses. In studies with N-nitrosocompounds, no GST-P+ foci in the rat livers was detected after the treatment at low doses, on the contrary, at high doses DEN and DMN induced their development. In conclusion, DNA-reactive genotoxic agents such as heterocyclic amines MeIQx, IQ and PhIP, and N-nitrosocompounds DEN and DMN were concluded to exert a threshold, at least practical, with respect to their carcinogenicity.

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Altered Gene Expression in Rat Colonic Adenocarcinomas Induced in an Azoxymethane plus 2-Amino-1-Methyl-6-Phenylimidazo[4,5-<i>b</i>]- Pyridine Initiation-Promotion Model

Cited by 5 publications

References 57 publications

Mthfd1 is a modifier of chemically induced intestinal carcinogenesis

Mthfd1 is a modifier of chemically induced intestinal carcinogenesis

Mouse models for the study of colon carcinogenesis

Threshold in Carcinogenicity of Genotoxic Carcinogens

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