Altered gene expression in rat colonic adenocarcinomas induced in an azoxymethane plus 2-amino-1-methyl-6-phenylimidazo[4,5-b]- pyridine initiation-promotion model.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant food-derived mutagenic/carcinogenic heterocyclic amine (HCA), has attracted particular attention as a probable human colon carcinogen. Some studies have shown that PhIP administered in the post-initiation phase is able to enhance rat colon carcinogenesis remarkably. To determine whether this genotoxicant leaves a DNA footprint in colon carcinogenesis, 6-week-old male F344 rats were first subcutaneously injected with azoxymethane (AOM) and then continuously treated with various doses (0-200 ppm) of PhIP added to their diet. Animals were killed at week 36 for histopathological examination, and colonic adenocarcinomas derived from animals receiving 0, 50 and 200 ppm PhIP were subjected to a novel three-dimensional (3D)-microarray and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. A total of five candidate genes were identified in adenocarcinomas following 200 ppm of PhIP and AOM initiation, with a dose-dependent increment. Among them, Stat1 (signal transducer and activator of transcription 1) and VEGFc (vascular endothelial growth factor c) demonstrated statistically significant upregulation by real-time RT-PCR. In addition, HSP90 (heat shock protein 90) and VEGFa showed a non-significant tendency to increase. In summary, overexpression of Stat1, VEGF and other genes could be involved in PhIP-enhanced colon tumorigenesis in the post-initiation phase.
Doi
Kenichiro
K
Department of Pathology, Osaka City University Medical School, Osaka, Japan. kenchan@med.osaka-cu.ac.jp
Hagihara
Atsushi
A
Wei
Min
M
Yunoki
Takayuki
T
Fukushima
Shoji
S
Wanibuchi
Hideki
H
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007093:Imidazoles / Q000633:toxicity*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D002273:Carcinogens; D007093:Imidazoles; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D001397:Azoxymethane