Knockout of the 15 kDa Selenoprotein Protects against Chemically-Induced Aberrant Crypt Formation in Mice

Abstract

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.

Deficiency of the 15-kDa selenoprotein led to cytoskeleton remodeling and non-apoptotic membrane blebbing through a RhoA/ROCK pathway

“…Sep15 has been implicated in cancer development [6,8,12,13,18,19]. However, the mechanistic role of Sep15 during cancer development is not fully understood.…”

“…The knockdown of Sep15 mRNA in a colon cancer cell line led to the inhibition of colony formation, tumor growth, and lung metastasis [17,18]. SEP15 knockout in mice prevented chemically induced aberrant crypt formation presumably by regulating guanylate binding protein-1 [19]. …”

Selenoproteins: Molecular Pathways and Physiological Roles

“…In addition, Sep15 has been implicated in preventing liver (192), prostate (147), breast (264), and lung cancers (8). However, other studies demonstrated a role of Sep15 in promoting some types of cancer including colon cancer (153,347 (294). However, the exact function of SelM and its physiological roles in the brain as well as in other tissues remain unclear.…”

Selenium. Role of the Essential Metalloid in Health

“…An increase of Sep15 expression in colon cancer has been found [118], and targeted down-regulation of Sep15 inhibited growth of colon cancer cells [119]. Additionally, Sep15 knockout mice form significantly fewer carcinogen-induced aberrant crypt foci in colonic epithelia in vivo compared to controls [120]. Thus, the tumor-suppressor activity or oncogenic activity of Sep15 may be tissue-dependent.…”