Parp-1 deficiency implicated in colon and liver tumorigenesis induced by azoxymethane.
Poly(ADP-ribose) polymerase-1 (Parp-1) is activated by DNA strand breaks and functions in the maintenance of genomic integrity and cell death control. On the other hand, Parp-1 is also involved in transcriptional regulation of various genes, and the relationship between Parp-1 deficiency and susceptibility to tumorigenesis has not been fully elucidated. In the present study, Parp-1(-/-) mice, harboring exon 1 disruption in Parp-1, and Parp-1(+/+) animals were administered azoxymethane (AOM) at a dose of 10 mg/kg body weight once a week for 6 weeks. At 30 weeks after the first carcinogen treatment, mice were sacrificed. The incidence of animals bearing either adenomas or adenocarcinomas in the colon and the average number of colon tumors per mouse were significantly higher in Parp-1(-/-) mice than in Parp-1(+/+) animals. beta-Catenin accumulation was observed in 43/44 of Parp-1 (-/-) tumors and 19/21 of the Parp-1(+/+) tumors and was not statistically different between the genotypes. This suggests that most tumors developed through a pathway involving the alteration of Wnt-beta-catenin signaling in both Parp-1(-/-) and Parp-1(+/+) mice. In the liver, where AOM is primarily activated, the incidence of animals bearing nodules and the average number of nodules per section were significantly increased in Parp-1(-/-) mice compared with Parp-1(+/+) mice. Therefore, the results indicate that susceptibility to AOM-induced tumorigenesis in the colon and also in the liver is enhanced in Parp-1(-/-) mice, and Parp-1 could have a substantial role in colon and liver tumorigenesis.
Nozaki
Tadashige
T
Biochemistry Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
Fujihara
Hisako
H
Watanabe
Masatoshi
M
Tsutsumi
Masahiro
M
Nakamoto
Kentaro
K
Kusuoka
Osamu
O
Kamada
Nobuo
N
Suzuki
Hiroshi
H
Nakagama
Hitoshi
H
Sugimura
Takashi
T
Masutani
Mitsuko
M
D000230:Adenocarcinoma / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D000236:Adenoma / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D006720:Homozygote; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency*; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D002273:Carcinogens; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D015534:Trans-Activators; D051176:beta Catenin; D011065:Poly(ADP-ribose) Polymerases; D001397:Azoxymethane