DNA methylation of the pepsinogen 1 gene during rat glandular stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine or catechol.
The methylation patterns of the rat pepsinogen 1 (Pg1) gene in preneoplastic and neoplastic stomach lesions induced by genotoxic N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or the non-genotoxic carcinogen catechol were investigated. Male WKY/Ncrj rats were given MNNG in their drinking water (50 mg/l) for 30 weeks or 0.8% catechol throughout the experiment (60 weeks). MNNG induced Pg1 altered pyloric glands (PAPG), adenomatous hyperplasias and well-differentiated adenocarcinomas. Catechol also induced PAPG and adenomatous hyperplasias although cancers did not develop. Adenomatous hyperplasias and adenocarcinomas all consisted of gastric type cells resembling surface mucous cells or pyloric gland cells with little or no Pg1 expression. In MNNG-induced stomach cancers generally lacking Pg1, altered Pg1 gene methylation was observed with both CCGG and GCGC sites being methylated more than normal pyloric mucosa. MNNG or catechol-induced adenomatous hyperplasias also demonstrated essentially the same methylation changes in the CCGG, but not in the GCGC sites. In the mucosa containing PAPG in groups treated with MNNG or catechol the methylation patterns of the Pg1 gene were quite similar to those of normal pyloric mucosa, although the CCGG sites tended to demonstrate slightly increased methylation. The results suggest that the altered methylation of the Pg1 gene observed in stomach cancers is acquired early in the carcinogenic process and progressive methylation changes occur with tumor development.
Tatematsu
M
M
First Department of Pathology, Nagoya City University, Medical School, Japan.
Ichinose
M
M
Tsukada
S
S
Kakei
N
N
Takahashi
S
S
Ogawa
K
K
Hirose
M
M
Furihata
C
C
Miki
K
K
Kurokawa
K
K
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002396:Catechols; D004247:DNA / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D008297:Male; D008745:Methylation; D008769:Methylnitronitrosoguanidine; D010435:Pepsinogens / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D002396:Catechols; D010435:Pepsinogens; D008769:Methylnitronitrosoguanidine; D004247:DNA; C034221:catechol