A Function Variant at miR-501 Alters Susceptibility to Hepatocellular Carcinoma in a Chinese Han Population

Abstract

Backgroud/Aims: Previous studies have shown that miR-501 is involved in the development of hepatocellular carcinoma (HCC) by promoting cell proliferation through CYLD. From the published MirSNP database that enrolls all single nucleotide polymorphisms(SNPs) of microRNA (miRNA), we found an interesting SNP (rs112489955, G>A) located in the mature region of miR-501. Methods: We performed a case-control study focusing on the predicted SNP located in miRNA-501 to investigate the further relationship of the SNPs with miRNAs among HCC patients. Genotyping, real time PCR assay, cell transfection and the dual luciferase reporter assay were used in our study. Results: Bioinformatic analysis indicated that this SNP would inhibit the binding of miR-501 to CYLD. In a case-control study, subjects with the variant genotypes (AG, GG) showed a significantly increased risk of HCC relative to AA carriers. A significant association of miR-501 variant genotypes with enhanced tumor growth was also observed. Further functional analyses indicated that patients with the AA genotype might attenuate the level of CYLD compared to that regulated by miR-501 with the GG genotype. A dual luciferase reporter assay also confirmed that miR-501 with the A allele had reduced binding to CYLD. We further confirmed a suppression of cell proliferation and promotion of apoptosis in SMMC-7721 and Hep3B cell lines treated with the AA genotype. Conclusions: We identified a novel SNP located in miR-501 acting as an important factor of the HCC susceptibility by modulating miR-501 and CYLD levels.