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

• Main Authors: Jyotsna D. Godavarthi, Shahrazad Polk, Lisa Nunez, Amruthesh Shivachar, Nancy L. Glenn Griesinger, Angabin Matin
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Biology
• Subjects: splicing factor 1 (SF1); APC (adenomatous polyposis coli); polyp
• Online Access: https://www.mdpi.com/2079-7737/9/11/398
• ISSN: 2079-7737

Background: Splicing factor 1 (SF1) is a conserved alternative splicing factor expressed in many different mammalian cell types. The genetically modified <i>Sf1+/−</i> (or <i>Sf1^β-geo/+</i>) 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 <i>Wnt</i> signaling pathway and is a frequent genetic event in colon cancers. Mice with a point mutation in the <i>Apc</i> gene (<i>Apc^Min/+</i>) 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 <i>Apc^Min/+</i> mutation. Methods: We utilized mice genetically deficient for expression of SF1 to assess how SF1 levels affect intestinal tumorigenesis. We crossed <i>Apc^Min/+</i> to <i>Sf1+/−</i> mice to generate a cohort of heterozygous mutant <i>ApcMin/+;Sf1+/−</i> mice and compared intestinal polyp development in these mice to that in a control cohort of sibling <i>Apc^Min/+</i> mice. We compared total polyp numbers, sizes of polyps and gender differences in polyp numbers between <i>ApcMin/+;Sf1+/−</i> and <i>Apc^Min/+</i> mice. Results: Our results showed that <i>Apc^Min/+</i> mice with lower SF1 expression developed 25–30% fewer intestinal polyps compared to their <i>Apc^Min/+</i> siblings with normal SF1 levels. Interestingly, this difference was most significant for females (<i>ApcMin/+;Sf1+/−</i> and <i>Apc^Min/+</i> females developed 39 and 55 median number of polyps, respectively). Furthermore, the difference in polyp numbers between <i>ApcMin/+;Sf1+/−</i> and <i>Apc^Min/+</i> 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 <i>Apc^Min/+</i> driver mutation in the mouse intestine. Thus, therapeutic lowering of SF1 levels in the intestine could attenuate intestinal polyp development.