Combination of selenium and green tea improves the efficacy of chemoprevention in a rat colorectal cancer model by modulating genetic and epigenetic biomarkers

Dietary supplementation of selenium and green tea holds promise in cancer prevention. In this study, we evaluated the efficacies of selenium and green tea administered individually and in combination against colorectal cancer in an azoxymethane (AOM)-induced rat colonic carcinogenesis model and determined the underlying mechanisms of the protection. Four-week old Sprague-Dawley male rats were fed with diets containing 0.5% green tea extract, 1ppm selenium as selenium-enriched milk protein, or combination of 1ppm selenium and 0.5% green tea extract. Animals received 2 AOM (15 mg/kg) treatments to induce colonic oncogenesis. Rats were killed 8 or 30 wk later after the last AOM to examine the effect of dietary intervention on aberrant crypt foci (ACF) formation or tumor development. On sacrifice, colons were examined for ACF and tumors, the mRNA levels of SFRP5 and Cyclin D1, and the proteins levels of ß-catenin, COX-2, Ki-67, DNMT1 and acetyl histone H3. The combination of selenium and green tea resulted in a significant additive inhibition of large ACF formation, this effect was greater than either selenium or green tea alone, P,0.01; the combination also had a significant additive inhibition effect on all tumor endpoints, the effect of the combination diet on tumor incidence, multiplicity and size was greater than selenium or green tea alone, P,0.01. Rats fed the combination diet showed marked reduction of DNMT1 expression and induction of histone H3 acetylation, which were accompanied by restoration of SFRP5 mRNA in normal-appearing colonic crypts. The combination diet also significantly reduced ß-catenin nuclear translocation, Cyclin D1 expression and cell proliferation. These data show, for the first time, that combination of selenium and green tea is more effective in suppressing colorectal oncogenesis than either agent alone. The preventive effect is associated with regulation of genetic and epigenetic biomarkers implicated in colonic carcinogenesis

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Influence of selenised dairy proteins on biomarkers of colon cancer risk

Abstract Selenium is an essential trace element for mammals, and a component of at least 25 selenoproteins which incorporate the amino acid selenocysteine (Sec). These proteins include a number with oxidoreductase functions. An examination of the selenoproteins and their influence on carcinogenesis in an animal model may assist in determining their relevance in chemoprevention. Food sources offer a number of organic forms of selenium, with selenomethionine a common component, as in selenised yeasts. A selenium-rich dairy protein product has been developed (TaturaBioSe, Tatura Milk Industries, Tatura, Victoria) which could improve selenium status in populations considered marginal or deficient. It could also provide higher intakes (e.g. several fold above recommended dietary intake recommendations) of potential benefit as chemopreventive to those at greater risk of some selenium-responsive diseases, such as some sporadic colorectal cancers. Clinical studies are showing it to be a safe, palatable product for consumption in the form provided. Dairy protein selenium at 1 ppm in diet had a significant chemopreventive effect compared with control (0.05 ppm Se) in an azoxymethane model of colon cancer. Colon tumour incidence in rats was down by 29%, and tumour burden (colon tumours/rat) was halved, effects not observed when an equivalent Se concentration was provided as yeast selenium. When assessed by plasma Se concentration, this dairy protein form of selenium showed greater bioavailability (as assessed by plasma selenium) as well as efficacy in chemoprevention. Programmed cell death (apoptosis) was increased in colonic crypts and crypt height significantly diminished. The influence on early changes in carcinogenesis provides an insight into possible mechanism(s) of action. Histological and biochemical assays (e.g. monitoring oxidoreductase enzymes) could potentially provide early biomarkers with clinical relevance