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

Abstract

Testicular germ cell tumors (TGCT) originate from germ cells. The 129-Ter and M19 (129.MOLF-Chr19 consomic) mouse strains have extremely high incidences of TGCTs. We found that the expression levels of Sf1-encoded splicing factor 1 (SF1) can modulate the incidence of TGCTs. We generated mice with inactivated Sf1. Sf1 null mice (Sf1−/−) died before birth. Mice with one intact allele of Sf1 (Sf1+/−) were viable but expressed reduced levels of Sf1. When Sf1-deficient mice (Sf1+/−) were crossed to the 129-Ter and M19 strains, we observed decreased incidence of TGCTs in Sf1+/−;Ter and Sf1+/−;M19/+ mice compared with that in control cohorts. Therefore, Sf1 deficiency protects against TGCT development in both strains. Sf1 is expressed in the testes. We found that Sf1 levels vary significantly in the testes of inbred strains such as 129 and MOLF, and as such Sf1 is an oncogenic tumor-susceptibility factor from 129. Our results also highlight the complications involved in evaluating Sf1 levels and TGCT incidences. When a large number of tumor-promoting factors are present in a strain, the protective effect of lower Sf1 levels is masked. However, when the dosage of tumorpromoting factors is reduced, the protective effect of lower Sf1 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 Sf1 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.

Mouse models of testicular germ cell tumors

“…Despite this protective effect on TGCT formation, all mutant males are sterile due to a complete germ cell deficiency (R. Zhu et al, 2010). This phenotype is similar as those observed in the {Ter/Ter; Bax -/ + } males suggesting a common pathway involving both SF1 and BAX on PGC deficiency in 129-Ter/Ter mice.…”

“…Liu et al, 2001). Interestingly, Sf1 deficiency (heterozygous Sf1 -/ + ) in 129-M19/+ males reduces the incidence of TGCTs (R. Zhu et al, 2010), suggesting that Sf1 may be one of the TGCT enhancer genes on chromosome 19. D19Bwg1357e is a predicted gene down-regulated in the gonads of MOLF strain mice (R. Zhu et al, 2007).…”

“…The double {Ter/Ter; Sf1 -/ + } mutants in the 129 strain have a 2-fold reduction in risk due to a reduced frequency of bilateral tumors (R. Zhu et al, 2010). Despite this protective effect on TGCT formation, all mutant males are sterile due to a complete germ cell deficiency (R. Zhu et al, 2010).…”

Chromosome substitution strains: gene discovery, functional analysis, and systems studies

“…The five QTLs that were detected showed pervasive epistatic effects depending on the genetic constitution of the congenic strain. Subsequent expression studies with these congenic strains revealed strong candidate genes for several of these QTLs (Zhu et al 2010). Presumably, the large number of susceptibility genes and their interactions account for the broad QTL localization in the CSS cross.…”

“…These discoveries include the splicing factor 1 in control of TGCT susceptibility (Zhu et al 2010); solute receptor Slc35b4 as a regulator of diet-induced obesity, insulin resistance, and gluconeogenesis (Yazbek et al 2011); the TNNi3 kinase Tnni3k , fucose-1 phosphate guanylyltransferase Fpgt , or H28 genes in control of viral myocarditis (Wiltshire et al 2011); tomosyn-2 (syntaxin binding protein 5-like, STXBL5L ) as a negative regulator of insulin secretion (Bhalnagar et al 2011); lymphocyte antigen 6 complex, locus A Ly6a as a regulator of novelty responsiveness (de Jong et al 2011); transcription factor AP2 alpha Tcfap2a in control of voluntary physical activity through a dopaminergic pathway (Yang et al 2012); a long noncoding RNA (Rubie) upstream of Bmp4 in vestibular development (Roberts et al 2012); and the voltage-gated potassium Cntnap2 gene in control of diet-induced obesity (Buchner et al 2012). These early results clearly show the efficacy of gene discovery with CSSs.…”