Genetic Variations In Cell Cycle And Apoptosis Pathways Affect Bladder Cancer Risk

Objective:Prostate cancer is the most common malignant tumor of urinary system in developed countries in Europe and America,and bladder cancer?BC?ranks second.While in China,bladder cancer is one of the most frequent malignacies of the urinary tract.Meanwhile,the incidence of BC is significantly different in gender,and is higher in men than in women,is the first of men,have increased by years,with a high degree of genetic instability and high recurrent.Although the mortality of BC is lower and patients have longer survival than any other malignant tumor,the recurrence caused by multiple surgeries,may seriously affect the life quality of patients.Therefore,in order to reduce the incidence of BC and increase the cure rate,we should pay more attention to study the pathogenesis of BC,then to improve patient prognosis and quality of life.The key genes which related to cell-cycle and apoptosis pathways play important roles in bladder cancer.The regulation of cell cycle and apoptosis pathways can be controlled by epigenetics.As an important aspectof epigenetics,micro-RNAs?miRNAs?are a kind of small noncoding and single-stranded RNA moleules?22-25nt?,which noramlly regulate gene expression through binding the 3'untranslated regions?3'UTR?of messenger RNA?mRNA?.Single nucleotide polymorphism?SNP?is the most common genetic variation in humans,and is also with a variation frequency of more than1%,which can cause changes of gene structure and function.The SNPs in the3'UTRofgenesmayimpactmiRNA-mRNAbindingcapacity.Population-based case-control study on molecular epidemiology was carried out in this study,we selected SNPs in the 3'-UTR of cell-cycle and apoptosis pathways,to assess the association between genetic variations in cell cycle and apoptosis pathways and bladder cancer risk..Methods:578 patients with bladder cancer cases and 1006 cancer-free controls frequency-matched by age and sex were recruited in this study,to selecte SNPs in the 3'-UTR of cell-cycle and apoptosis pathways,then genotyped them.Using dual luciferase reporter gene assay to validate the biological function of SNPs,the logistic regression was also used to assess the the association between each polymorphism and biadder cancer.Results:We found 5 SNPs might change the binding ability of mi RNA to their target genes,which were rs7431,rs41372847,rs41275750,rs2864,rs4570,among them PPP3CC rs7431 A>G located in the 3'UTR with the minimum p value(p=5.74*10^-4).Analysis revealed that rs7431 desrupted miR-212 and miR-132 targeting sites.Logistic regression showed there was an association between bladder cancer and the PPP3CC rs7431 A>G polymorphism,it significantly decreased risk of cancer,with an odds ratio?OR?of 0.76?95%confidence interval?CI?=0.66-0.89,p=5.74*10^-4?.Luciferase report assay showed that both miR-212 and miR-132 could result in increased PPP3CC expression levels in the construct with G allele compared to the A allel.Conclusions:PPP3CC rs7431 could change miRNA binding ability of miR-212 and miR-132,then decrease the risk of bladder cancer.