rs2294008T, a risk allele for gastric and gallbladder cancers, suppresses the PSCA promoter by recruiting the transcription factor YY1.

Previous genomewide association studies identified prostate stem cell antigen (PSCA) as a gastric cancer (GC) susceptibility gene and showed an association between GC and the T allele of the single nucleotide polymorphism rs2294008 (C/T) in this gene. The protein product of this gene inhibits cell growth, and the T allele significantly suppresses the transcriptional activity of the -3.2 kb PSCA upstream region. However, the mechanism remains unknown. In this study, we conducted reporter assays using the PSCA upstream region containing the C allele and identified the region from -200 to +38 bp of the transcription initiation site of the gene as a critical region of the -3.2 kb PSCA upstream region. We found that introducing the T allele at rs2294008 generated a consensus binding sequence for the Polycomb group transcription factor Yin Yang 1 (YY1) and that disruption of the consensus sequence restored the transcriptional activity to the -3.2 kb PSCA upstream region. These findings imply that the T allele significantly suppresses PSCA expression in vivo by recruiting YY1 to its promoter, which eventually predisposes gastric epithelial cells to GC development.

His595Tyr polymorphism in the methionine synthase reductase (MTRR) gene is associated with pancreatic cancer risk.

BACKGROUND & AIMS: This study attempts to elucidate a part of the genetic predisposition to the sporadic invasive ductal adenocarcinoma of the pancreas focusing on the genes implicated in the gene-environment interactions in carcinogenesis. METHODS: First, 227 single nucleotide polymorphisms (SNPs) of 46 genes were genotyped on 198 cases and 182 controls. The SNPs, which showed a significant association, were further genotyped on additional samples to perform a joint analysis (total 317 cases vs 1232 controls). The gene selected by joint analysis was resequenced for a high-density SNP typing and a haplotype analysis on 702 cases and 785 controls. Function of the risk and wild-type haplotypes was assessed using cells transfected with complementary DNA (cDNA). RESULTS: The joint analysis with multiple testing adjustment identified 2 SNPs on the methionine synthase reductase (MTRR) gene: rs162049 (intronic SNP), Fisher exact test, P = .0018; OR, 1.33; 95% CI: 1.11-1.60 and rs10380 (His595Tyr), Fisher exact test, P = .0063; OR, 1.45; 95% CI: 1.11-1.88. The SNPs remained significant in the recessive model after the permutation test for multiple testing (rs162049, P = .024; rs10380, P = .023) in the high-density analysis. Stable transfectants of the risk haplotype MTRR cDNA showed significantly elevated homocysteine levels in a culture medium, a lower level of the LINE-1 methylation, and a lower expression of the MTRR protein than did the transfectants with the wild-type haplotype cDNA. CONCLUSIONS: Our study suggested a common missense SNP of the MTRR gene as a novel pancreatic cancer susceptibility factor with a functional significance in folate-related metabolism and the genome-wide methylation status.

A new synbiotic, Lactobacillus casei subsp. casei together with dextran, reduces murine and human allergic reaction.

We studied the development of atopic dermatitis-like skin lesions in NC/Nga mice and the allergic symptoms and blood patterns of healthy volunteers during the cedar (Cryptomeria japonica) pollen season in Japan following oral administration of a new synbiotic, Lactobacillus casei subsp. casei together with dextran. The combination of L. casei subsp. casei and dextran significantly decreased clinical skin severity scores and total immunoglobulin E levels in sera of NC/Nga mice that had developed picryl chloride-induced and Dermatophagoides pteronyssinus crude extract-swabbed atopic dermatitis-like skin lesions. During the most common Japanese cedar pollen season, synbiotic L. casei subsp. casei and dextran in humans led to no significant changes in total nasal and ocular symptom scores, in the levels of cedar pollen-specific immunoglobulin E, interferon-gamma and thymus and activation regulated chemokine or in the number of eosinophils in sera, whereas the placebo group showed a tendency for increased levels of cedar pollen-specific immunoglobulin E, thymus and activation regulated chemokine and number of eosinophils, and a decrease in interferon-gamma levels. Thus, the oral administration of synbiotic L. casei subsp. casei together with dextran appears to be an effective supplement for the prevention and treatment of allergic reactions.

Structure-activity relationships of the inhibitory effects of flavonoids on P-glycoprotein-mediated transport in KB-C2 cells.

We studied the effects of flavonoids, naringenin (flavanone), baicalein (flavone), kaempferol, quercetin, myricetin, morin, and fisetin (flavonols) as well as two glycosides of quercetin on P-glycoprotein (P-gp) function in multidrug-resistant P-gp overexpressing KB-C2 cells. Flavonoids such as kaempferol and quercetin increased the accumulation of rhodamine-123 dependent on their chemical structure. Analysis by flow cytometry indicated that the increase in substrate accumulation was due to the inhibition of substrate efflux. Naringenin, which lacks the 2,3-double bond in the C ring, had no effect, although it was more hydrophobic than myricetin, fisetin and morin. Therefore, the planar structure of the flavonoids seemed to be important for their interaction with P-gp. The effects of other flavonoids on the accumulation of daunorubicin were in the order of kaempferol>quercetin, baicalein>myricetin>fisetin, morin. Quercetin-3-O-glucoside and rutin had no effect. The order of the effects corresponded with that of the partition coefficients. Difference in the number and position of hydroxyl groups in flavonoid molecules by themselves seemed to have little effect. These results suggested that hydrophobicity as well as planar structure is important for the inhibitory effects of flavonoids on P-gp-mediated transport.