Impact of 15kDa Selenoprotein and Dietary Selenium on Initiation and Promotion in Colorectal Carcinogenesis

Abstract

The micronutrient selenium (Se) largely exerts its biological effects through incorporation into selenoproteins. Several selenoproteins, including the 15kDa selenoprotein (Sep15), are thought to play roles in both cancer prevention and promotion. Previously, Sep15 knockout (KO) mice were shown to be resistant to formation of chemically‐induced pre‐neoplastic lesions. In our current study, Sep15 KO mice and littermate controls were maintained on deficient (0.02 ppm) or adequate (0.1 ppm) dietary Se. Mice were injected with azoxymethane (AOM) or saline, followed by treatment with dextran sulfate sodium (DSS) or water, to initiate and promote colon tumorigenesis. Formation of pre‐neoplastic lesions was again dramatically reduced in Sep15 KO mice compared to littermate controls, independent of dietary Se levels. Fewer Sep15KO mice developed tumors when Se‐deficient, but formed a similar number of tumors as controls when Se‐replete. Tumor mass itself appeared to be similar in control and Sep15KO mice when Se‐deficient, and slightly larger in Sep15 KO mice when Se‐replete. This suggests that Sep15 KO mice may be protected against AOM‐induced cancer initiation, but not against AOM/DSS‐induced tumor formation, and that dietary Se may modify the outcome. To assess cancer initiation, hepatic mRNA expression of CYP2E1, the enzyme responsible for activating AOM to its mutagenic form, was quantitated, and found to be significantly reduced in untreated Sep15 KO mice compared to littermate controls in Se‐deficient conditions, whereas no differences were detected in AOM/DSS‐treated mice. Interestingly, there also appear to be Se‐mediated differences in hepatic CYP2E1 expression. Inflammation is a strong tumor promoter in colorectal cancer, and pro‐inflammatory serum cytokines were generally higher in mice treated with AOM/DSS compared to those injected with saline. Interestingly, serum interferon‐γ, TNFα and Cxcl1 levels did not differ between Sep15 KO mice and controls, regardless of dietary Se or inflammation treatment. Other cytokines are currently being assessed in serum, colorectal epithelia, and spleens.Support or Funding InformationNCI Intramural support; NIH CA080946 (VNG); Office of Dietary Supplements; Towson University Jess & Mildred Fisher Endowed Chair (PAT)