Increased susceptibility of Sf1+/- mice to azoxymethane-induced colon tumorigenesis

Abstract

Aberrant transactivation of a certain set of target genes by the β-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 β-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 β-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 mm3 per female [P = 0.0008, 11.3 ± 3.4 versus 0.6 ± 0.2 mm3 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 β-catenin-mediated regulation of proliferation and differentiation of intestinal epithelial cells. © 2007 Japanese Cancer Association.