Deficiency of Splicing Factor 1 (SF1) Reduces Intestinal Polyp Incidence in <i>Apc^Min/</i>⁺ Mice

Abstract

Background: Splicing factor 1 (SF1) is a conserved alternative splicing factor expressed in many different mammalian cell types. The genetically modified Sf1+/− (or Sf1β-geo/+) mice express reduced levels of SF1 protein in mouse tissues, including in cells of the intestines. Mutational inactivation of human adenomatous polyposis coli (APC) gene deregulates the Wnt signaling pathway and is a frequent genetic event in colon cancers. Mice with a point mutation in the Apc gene (ApcMin/+) also develop numerous intestinal polyps at a young age. Our aim was to determine the effect of reduced SF1 levels on polyp development due to the strong driver ApcMin/+ mutation. Methods: We utilized mice genetically deficient for expression of SF1 to assess how SF1 levels affect intestinal tumorigenesis. We crossed ApcMin/+ to Sf1+/− mice to generate a cohort of heterozygous mutant ApcMin/+;Sf1+/− mice and compared intestinal polyp development in these mice to that in a control cohort of sibling ApcMin/+ mice. We compared total polyp numbers, sizes of polyps and gender differences in polyp numbers between ApcMin/+;Sf1+/− and ApcMin/+ mice. Results: Our results showed that ApcMin/+ mice with lower SF1 expression developed 25–30% fewer intestinal polyps compared to their ApcMin/+ siblings with normal SF1 levels. Interestingly, this difference was most significant for females (ApcMin/+;Sf1+/− and ApcMin/+ females developed 39 and 55 median number of polyps, respectively). Furthermore, the difference in polyp numbers between ApcMin/+;Sf1+/− and ApcMin/+ mice was significant for smaller polyps with a size of 2 mm or less, whereas both groups developed similar numbers of larger polyps. Conclusions: Our results suggest that lower SF1 levels likely inhibit the rate of initiation of polyp development due to ApcMin/+ driver mutation in the mouse intestine. Thus, therapeutic lowering of SF1 levels in the intestine could attenuate intestinal polyp development.

Keywords

• splicing factor 1 (SF1)
• APC (adenomatous polyposis coli)
• polyp