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Updated: Jul 11, 2026
Modeling Colitis-Associated Cancer with Azoxymethane (AOM) and Dextran Sulfate Sodium (DSS)
Published on: September 11, 2012
Increased susceptibility of Sf1(+/-) mice to azoxymethane-induced colon tumorigenesis
Miki Shitashige1, Reiko Satow, Kazufumi Honda
1Chemotherapy Division and Cancer Proteomics Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Abstract:
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.
Insights
Splicing factor-1 (SF1) plays a key role in preventing colorectal cancer. Mice with reduced SF1 showed increased tumor development after chemical exposure, highlighting SF1's protective function in the intestine.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Aberrant Wnt/beta-catenin signaling drives colorectal carcinogenesis.
- Splicing factor-1 (SF1) was previously identified as a component of the beta-catenin/T-cell factor-4 complex.
- SF1 overexpression inhibited beta-catenin/T-cell factor-4 activity and cell proliferation in vitro.
Purpose of the Study:
- To investigate the in vivo role of SF1 in colorectal carcinogenesis.
- To determine if SF1 deficiency influences susceptibility to chemically induced colon tumors.
Main Methods:
- Generation of SF1-knockout mice using gene trapping.
- Administration of azoxymethane (AOM) to heterozygous (Sf1(+/-)) and wild-type (Sf1(+/+)) mice.
- Quantification of colon tumor incidence and volume post-AOM treatment.
Main Results:
- SF1 knockout mice (Sf1(-/-)) exhibited embryonic lethality before embryonic day 8.5.
- Heterozygous Sf1(+/-) mice showed significantly increased numbers and volumes of colon tumors after AOM treatment compared to Sf1(+/+) mice.
- This increased susceptibility was observed in both male and female mice.
Conclusions:
- SF1 is crucial for suppressing in vivo colon tumorigenesis.
- SF1 is involved in the beta-catenin-mediated regulation of intestinal epithelial cell proliferation and differentiation.
- Reduced SF1 levels enhance susceptibility to colorectal cancer initiation.
