Evidence suggests that
selenium has
cancer preventive properties that are largely mediated through
selenoproteins. Our previous observations demonstrated that targeted down-regulation of the 15 kDa
selenoprotein (Sep15) in murine
colon cancer cells resulted in the reversal of the
cancer phenotype. The present study investigated the effect of Sep15 knockout in mice using a chemically-induced
colon cancer model. Homozygous Sep15 knockout mice, and wild type littermate controls were given four weekly
subcutaneous injections of
azoxymethane (10 mg/kg). Sep15 knockout mice developed significantly (p<0.001) fewer
aberrant crypt foci than controls demonstrating that loss of Sep15 protects against
aberrant crypt foci formation. Dietary
selenium above adequate levels did not significantly affect
aberrant crypt foci formation in Sep15 knockout mice. To investigate molecular targets affected by loss of Sep15, gene expression patterns in colonic mucosal cells of knockout and wild type mice were examined using microarray analysis. Subsequent analyses verified that guanylate binding protein-1 (GBP-1)
mRNA and
protein expression were strongly upregulated in Sep15 knockout mice. GBP-1, which is expressed in response to
interferon-γ, is considered to be an activation marker during inflammatory diseases, and up-regulation of GBP-1 in humans has been associated with a highly significant, increased five-year survival rate in
colorectal cancer patients. In agreement with these studies, we observed a higher level of
interferon-γ in plasma of Sep15 knockout mice. Overall, our results demonstrate for the first time, that Sep15 knockout mice are protected against chemically-induced
aberrant crypt foci formation and that Sep15 appears to have oncogenic properties in colon
carcinogenesis in vivo.