Genetic variants in N6-methyladenosine are associated with bladder cancer risk in the Chinese population

• Published in: Archives of toxicology Vol. 95; no. 1; pp. 299 - 309
• Main Authors: Liu, Hanting, Gu, Jingjing, Jin, Yu, Yuan, Qi, Ma, Gaoxiang, Du, Mulong, Ge, Yuqiu, Qin, Chao, Lv, Qiang, Fu, Guangbo, Wang, Meilin, Chu, Haiyan, Yuan, Lin, Zhang, Zhengdong
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2021; Springer Nature B.V
• Subjects: Apoptosis; Biomedical and Life Sciences; Biomedicine; Bladder; Bladder cancer; Cancer; Cell proliferation; Environmental Health; Genetic diversity; Genetic variance; Genotoxicity and Carcinogenicity; Health risks; mRNA; N6-methyladenosine; Nucleotides; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Regression analysis; Regression models; Risk management; RNA-binding protein; Single-nucleotide polymorphism; Superoxide dismutase; Switches; Tumor suppressor genes; Molecular epidemiology; methyladenosine; Susceptibility; Bladder cancer; N; N6-methyladenosine
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-020-02911-2

Recently N 6 -Methyladenosine (m 6 A) has been identified to guide the interaction of RNA-binding protein hnRNP C and their target RNAs, which is termed as m 6 A-switches. We systematically investigated the association between genetic variants in m 6 A-switches and bladder cancer risk. A two-stage case–control study was performed to systematically calculate the association of single nucleotide polymorphisms (SNPs) in 2798 m 6 A-switches with bladder cancer risk in 3,997 subjects. A logistic regression model was used to assess the effects of SNPs on bladder cancer risk. A series of experiments were adopted to explore the role of genetic variants of m 6 A-switches. We identified that rs5746136 (G > A) of SOD2 in m 6 A-switches was significantly associated with the reduced risk of bladder cancer (additive model in discovery stage: OR = 0.80, 95% CI 0.69–0.93, P  = 3.6 × 10 −3 ; validation stage: adjusted OR = 0.88, 95% CI 0.79–0.99, P  = 3.0 × 10 −2 ; combined analysis: adjusted OR = 0.85, 95% CI 0.78–0.93, P  = 4.0 × 10 −4 ). The mRNA level of SOD2 was remarkably lower in bladder cancer tissues than the paired adjacent samples. SNP rs5746136 may affect m 6 A modification and regulate SOD2 expression by guiding the binding of hnRNP C to SOD2, which played a critical tumor suppressor role in bladder cancer cells by promoting cell apoptosis and inhibiting proliferation, migration and invasion. In conclusion, our findings suggest the important role of genetic variants in m 6 A modification. SOD2 polymorphisms may influence the expression of SOD2 via an m 6 A-hnRNP C-dependent mechanism and be promising predictors of bladder cancer risk.