Persistence of gene expression changes in stomach mucosae induced by short-term N-methyl-N'-nitro-N-nitrosoguanidine treatment and their presence in stomach cancers.
Cancers induced by different carcinogens show distinct expression profiles. In addition to the specific alterations of tumor-related genes induced by specific carcinogens, it is possible that some initial responses induced by a carcinogen could persist for long periods and are consistently present in the cancers induced. We have analyzed the initial responses in the rat pyloric mucosae after treatment for 2 weeks with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Gene expression was monitored 1 day, 2 weeks and 4 weeks after MNNG treatment by oligonucleotide microarray analysis. Of the differentially expressed genes showing greater than three-fold difference 1 day after MNNG treatment, 143 and 26 genes were up- and down-regulated, respectively, in MNNG-induced stomach cancers. Among these genes, 25 and 6 genes were up- and down-regulated, respectively, in the histologically normal pyloric mucosae, even 4 weeks after cessation of MNNG treatment. Among the up-regulated genes, many genes involved in tissue remodeling (Spi15, Serpine1 and Fst) and cellular growth (Bdnf, Ros1 and Fgf10) were present. The six down-regulated genes included TGF-beta-inducible early growth response gene. These findings demonstrate that some expression changes induced by MNNG persist for a prolonged period and are present in cancers. Persistent expression changes are considered to be important for prediction of past carcinogen exposure, and could provide a molecular environment favorable for malignant transformation.
Yamashita
Satoshi
S
Carcinogenesis Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Nomoto
Tomoko
T
Abe
Masanobu
M
Tatematsu
Masae
M
Sugimura
Takashi
T
Ushijima
Toshikazu
T
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D008769:Methylnitronitrosoguanidine / Q000633:toxicity*; D009153:Mutagens / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000235:genetics*
D017931:DNA Primers; D009153:Mutagens; D008769:Methylnitronitrosoguanidine