A novel functional polymorphism of GSTM3 reduces clear cell renal cell carcinoma risk through enhancing its expression by interfering miR-556 binding.

Dysregulation of glutathione-S-transferase M3 (GSTM3) has been related to clear cell renal cell carcinoma (ccRCC) in our former study. GSTM3 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 GSTM3 single nucleotide polymorphisms (SNPs) and risk of ccRCC, and (2) the potential molecular mechanism accounting for its effects. 5 SNPs in 3'UTR of GSTM3 were initially genotyped in 329 cases and 420 healthy controls. A SNP-rs1055259 was found to be significantly associated with the susceptibility of ccRCC (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 microRNA (miR)-556 binding to 3'UTR of GSTM3 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 GSTM3 expression in G-allele cells was associated with ROS activity and ccRCC development. Taken together, this study indicated that a functional polymorphism of GSTM3 -rs1055259 reduced susceptibility of RCC in the Chinese population. It influenced GSTM3 protein synthesis by interfering miR-556 binding, subsequently suppressed ROS activity and ccRCC progression.