Qiang Zhang1,2, Wenying Wang3, Weidong Xu4, Mulong Du`1,2, Gaoxiang Ma1,2, Hanting Liu1,2, Haiyan Chu1,2, N A Tong1,2, Meilin Wang1,2, Jianfeng Shao5, Zhengdong Zhang6,2, Lin Yuan7,8, Jing Qian9. 1. Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, P.R. China. 2. Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, P.R. China. 3. Department of Urology, Beijing Friendship Hospital affiliated to Capital Medical University, Beijing, P.R. China. 4. Department of Urology, Yizheng Hospital, Drum Tower Hospital Group of Nanjing, Yizheng, P.R. China. 5. Department of Urology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, P.R. China. 6. Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, P.R. China drzdzhang@gmail.com qianjing998@163.com yuanlin47@126.com. 7. Department of Urology, Jiangsu Province Hospital of TCM, Nanjing, P.R. China drzdzhang@gmail.com qianjing998@163.com yuanlin47@126.com. 8. Department of Integrated Traditional Chinese and Western Medicine Tumor Research Lab, Nanjing, P.R. China. 9. Department of General surgery, Yizheng Hospital, Drum Tower Hospital Group of Nanjing, Yizheng, P.R. China drzdzhang@gmail.com qianjing998@163.com yuanlin47@126.com.
Abstract
BACKGROUND: Key genes related to cell cycle and apoptosis pathways play critical roles in bladder cancer. Single nucleotide polymorphisms (SNPs) in the 3'-untranslated regions (3'-UTR) of genes may impact microRNA (miRNA)-messenger RNA (mRNA) binding capacity and alter gene expression to contribute to the susceptibility of cancers. However, an association of genetic variations in cell cycle and apoptosis pathways with bladder cancer risk, has not been reported. MATERIALS AND METHODS: We selected SNPs in the 3'-UTR of cell cycle and apoptosis pathways genes and genotyped them with a case-control study consisting of 578 bladder cancer patients and 1,006 cancer-free subjects. Dual luciferase reporter gene assay was performed to validate the biological function of important SNPs. RESULTS: We found that 5 SNPs might change the binding ability of miRNA to their target genes, among which PPP3CC rs7431 A>G located in the 3'-untranslated regions with the minimum p-value (p=5.75×10-4). Analysis revealed that the rs7431 disrupted miR-212 and miR-132 targeting sites. Logistic regression revealed a significantly decreased risk of bladder cancer associated with the PPP3CC rs7431 A>G polymorphism with an odds ratio (OR) of 0.76 [95% confidence interval (CI)=0.66-0.89, p=5.75×10-4]. Luciferase report assay showed that both miR-212 and miR-132 could lead to significantly increased PPP3CC expression levels in the construct with the G allele compared to the A allele. CONCLUSION: PPP3CC rs7431 may alter miRNA binding ability of miR-212 and miR-132, and thus decrease bladder cancer risk. Copyright
BACKGROUND: Key genes related to cell cycle and apoptosis pathways play critical roles in bladder cancer. Single nucleotide polymorphisms (SNPs) in the 3'-untranslated regions (3'-UTR) of genes may impact microRNA (miRNA)-messenger RNA (mRNA) binding capacity and alter gene expression to contribute to the susceptibility of cancers. However, an association of genetic variations in cell cycle and apoptosis pathways with bladder cancer risk, has not been reported. MATERIALS AND METHODS: We selected SNPs in the 3'-UTR of cell cycle and apoptosis pathways genes and genotyped them with a case-control study consisting of 578 bladder cancerpatients and 1,006 cancer-free subjects. Dual luciferase reporter gene assay was performed to validate the biological function of important SNPs. RESULTS: We found that 5 SNPs might change the binding ability of miRNA to their target genes, among which PPP3CCrs7431 A>G located in the 3'-untranslated regions with the minimum p-value (p=5.75×10-4). Analysis revealed that the rs7431 disrupted miR-212 and miR-132 targeting sites. Logistic regression revealed a significantly decreased risk of bladder cancer associated with the PPP3CCrs7431 A>G polymorphism with an odds ratio (OR) of 0.76 [95% confidence interval (CI)=0.66-0.89, p=5.75×10-4]. Luciferase report assay showed that both miR-212 and miR-132 could lead to significantly increased PPP3CC expression levels in the construct with the G allele compared to the A allele. CONCLUSION:PPP3CCrs7431 may alter miRNA binding ability of miR-212 and miR-132, and thus decrease bladder cancer risk. Copyright
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