Data from Deficiency of Splicing Factor 1 Suppresses the Occurrence of Testicular Germ Cell Tumors

Abstract

<div>Abstract<p>Testicular germ cell tumors (TGCT) originate from germ cells. The 129-<i>Ter</i> and M19 (129.MOLF-Chr19 consomic) mouse strains have extremely high incidences of TGCTs. We found that the expression levels of <i>Sf1</i>-encoded splicing factor 1 (SF1) can modulate the incidence of TGCTs. We generated mice with inactivated <i>Sf1. Sf1</i> null mice (<i>Sf1</i>−/−) died before birth. Mice with one intact allele of <i>Sf1</i> (<i>Sf1</i>+/−) were viable but expressed reduced levels of <i>Sf1</i>. When <i>Sf1</i>-deficient mice (<i>Sf1</i>+/−) were crossed to the 129-<i>Ter</i> and M19 strains, we observed decreased incidence of TGCTs in <i>Sf1</i>+/−;<i>Ter</i> and <i>Sf1</i>+/−;M19/+ mice compared with that in control cohorts. Therefore, <i>Sf1</i> deficiency protects against TGCT development in both strains. <i>Sf1</i> is expressed in the testes. We found that <i>Sf1</i> levels vary significantly in the testes of inbred strains such as 129 and MOLF, and as such <i>Sf1</i> is an oncogenic tumor-susceptibility factor from 129. Our results also highlight the complications involved in evaluating <i>Sf1</i> levels and TGCT incidences. When a large number of tumor-promoting factors are present in a strain, the protective effect of lower <i>Sf1</i> levels is masked. However, when the dosage of tumor-promoting factors is reduced, the protective effect of lower <i>Sf1</i> levels becomes apparent. SF1 is involved in splicing of specific pre-mRNAs in cells. Alternate splicing generates the complex proteosome in eukaryotic cells. Our data indicate that <i>Sf1</i> levels in mouse strains correlate with their incidences of TGCTs and implicate the importance of splicing mechanisms in germ cell tumorigenesis. Cancer Res; 70(18); 7264–72. ©2010 AACR.</p></div>