Increased susceptibility of Sf1(+/-) mice to azoxymethane-induced colon tumorigenesis.
Aberrant transactivation of a certain set of target genes by the beta-catenin and T-cell factor-4 nuclear complex has been considered crucial for the initiation of colorectal carcinogenesis. We previously identified splicing factor-1 (SF1) as a novel component of the beta-catenin and T-cell factor-4 complex, and showed that the overexpression of SF1 inhibited the gene transactivational activity of the complex and markedly suppressed beta-catenin-evoked colony formation by human embryonic kidney 293 cells. However, the involvement of SF1 in the process of carcinogenesis in vivo remains unclear. In the present study, we established SF1-knockout mice using the gene trapping method. Homozygous mice (Sf1(-/-)) died during embryonic development before embryonic day (E)8.5, whereas heterozygous (Sf1(+/-)) mice were born alive and developed normally. Azoxymethane (AOM) was given at a dose of 10 mg/kg body weight once a week for 6 weeks to 7-week-old Sf1(+/-) and Sf1(+/+) mice. At 23 weeks after the start of AOM the average number (5.5 +/- 0.6 versus 2.2 +/- 0.2 in females [P = 0.003, Mann-Whitney U-test], 3.7 +/- 0.2 versus 1.7 +/- 0.7 in males [P = 0.014]) and volume of colon tumors per mouse (8.7 +/- 1.6 versus 2.2 +/- 0.5 mm(3) per female [P = 0.0008], 11.3 +/- 3.4 versus 0.6 +/- 0.2 mm(3) per male [P = 0.001]) were significantly higher in Sf1(+/-) than in Sf1(+/+) mice. The increased susceptibility of Sf1(+/-) mice to AOM-induced colon tumorigenesis indicates the crucial involvement of SF1 in the beta-catenin-mediated regulation of proliferation and differentiation of intestinal epithelial cells.
Shitashige
Miki
M
Chemotherapy Division and Cancer Proteomics Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Satow
Reiko
R
Honda
Kazufumi
K
Ono
Masaya
M
Hirohashi
Setsuo
S
Yamada
Tesshi
T
D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D004195:Disease Models, Animal; D005804:Genes, Lethal; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D007438:Introns; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics; D000072260:RNA Splicing Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D015533:Transcriptional Activation; D051176:beta Catenin / Q000502:physiology; D000099266:Engrailed 2 Protein
D001397:Azoxymethane; D017931:DNA Primers; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000072260:RNA Splicing Factors; D014157:Transcription Factors; D051176:beta Catenin; D000099266:Engrailed 2 Protein; C491514:Sf1 protein, mouse