A novel functional polymorphism of GSTM 3 reduces clear cell renal cell carcinoma risk through enhancing its expression by interfering miR‐556 binding

• Published in: Journal of cellular and molecular medicine Vol. 22; no. 6; pp. 3005 - 3015
• Main Authors: Wang, Ying, Yang, Zi‐Ying, Chen, Yi‐Huan, Li, Feng, Shen, Han, Yu, You, Huang, Hao‐Yue, Shen, Zhen‐Ya
• Format: Journal Article
• Language: English
• Published: Chichester John Wiley & Sons, Inc 01.06.2018
• Subjects: 3' Untranslated regions; Alleles; Binding sites; Clear cell-type renal cell carcinoma; Deoxyribonucleic acid; Detoxification; DNA; Gene expression; Genomes; Genotype & phenotype; Glutathione; Kidney cancer; miRNA; Polymorphism; Protein biosynthesis; Reactive oxygen species; Single-nucleotide polymorphism; Software; Transcription; Tumors; United States > US; China
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.13528

Abstract Dysregulation of glutathione‐S‐transferase M3 ( GSTM 3 ) has been related to clear cell renal cell carcinoma (cc RCC ) in our former study. GSTM 3 plays a pivotal role of detoxification and clearance of reactive oxygen species ( ROS ) in tumour tissues. This study aimed to examine: (1) the associations between GSTM 3 single nucleotide polymorphisms ( SNP s) and risk of cc RCC , and (2) the potential molecular mechanism accounting for its effects. 5 SNP s in 3′ UTR of GSTM 3 were initially genotyped in 329 cases and 420 healthy controls. A SNP ‐rs1055259 was found to be significantly associated with the susceptibility of cc RCC ( OR  = 0.59, 95% CI  = 0.41‐0.92; P  =   .019). The minor allele of rs1055259 (G allele) was associated with RCC risk. This SNP was predicted to affect micro RNA (miR)‐556 binding to 3′ UTR of GSTM 3 mRNA . To determine the functional impact, plasmid constructs carrying different alleles of rs1055259 were created. Compared to rs1055259 A‐allele constructs, cells transfected with rs1055259 G‐allele construct had higher transcriptional activity and were less responsive to miR‐556 changes and gene expression. Elevated GSTM 3 expression in G‐allele cells was associated with ROS activity and cc RCC development. Taken together, this study indicated that a functional polymorphism of GSTM 3 ‐rs1055259 reduced susceptibility of RCC in the Chinese population. It influenced GSTM 3 protein synthesis by interfering miR‐556 binding, subsequently suppressed ROS activity and cc RCC progression.