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

SIMPLE SUMMARY: Splicing factor 1 (SF1) is a widely expressed alternative splicing factor that is able to process each piece of genetic information to generate different types of messenger RNAs (or alternate messages). The alternate messages can generate proteins with slightly different structure or function in the cell. Thus, alternative splicing is responsible for the large diversity of proteins that can finely tune cellular function to the cells’ physiological state. Using mouse models for our study, we found that mice expressing reduced SF1 levels develop fewer intestinal polyps. Lowered SF1 levels appear to limit the initiation of polyps. Thus, our studies point to a novel approach for reducing intestinal polyp burden. ABSTRACT: Background: Splicing factor 1 (SF1) is a conserved alternative splicing factor expressed in many different mammalian cell types. The genetically modified Sf1+/− (or Sf1(β-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 (Apc(Min/+)) 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 Apc(Min/+) mutation. Methods: We utilized mice genetically deficient for expression of SF1 to assess how SF1 levels affect intestinal tumorigenesis. We crossed Apc(Min/+) 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 Apc(Min/+) mice. We compared total polyp numbers, sizes of polyps and gender differences in polyp numbers between ApcMin/+;Sf1+/− and Apc(Min/+) mice. Results: Our results showed that Apc(Min/+) mice with lower SF1 expression developed 25–30% fewer intestinal polyps compared to their Apc(Min/+) siblings with normal SF1 levels. Interestingly, this difference was most significant for females (ApcMin/+;Sf1+/− and Apc(Min/+) females developed 39 and 55 median number of polyps, respectively). Furthermore, the difference in polyp numbers between ApcMin/+;Sf1+/− and Apc(Min/+) 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 Apc(Min/+) driver mutation in the mouse intestine. Thus, therapeutic lowering of SF1 levels in the intestine could attenuate intestinal polyp development.