MAGI2-AS3 rs7783388 polymorphism contributes to colorectal cancer risk through altering the binding affinity of the transcription factor GR to the MAGI2-AS3 promoter

Abstract

Background: It has been indicated that the single nuclear polymorphisms (SNPs) in the long noncoding RNA (lncRNA) have association with colorectal cancer (CRC) susceptibility.

Methods: We enrolled 1078 cases with CRC and 1175 age- and gender-matched cancer-free controls to explore whether the polymorphisms in MAGI2-AS3 have associations with CRC risk. qRT-PCR, expression quantitative trait loci (eQTL) analyses, dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), flow cytometry, and transwell assays were performed to explore the specific mechanisms in which MAGI2-AS3 rs7783388 variation influenced the tumorigenesis of CRC.

Results: Subjects carrying rs7783388 GG genotype presented a higher risk of CRC compared with the AG/AA genotypes. Mechanistically, we found that the functional genetic variant of rs7783388 A > G decreased binding affinity of transcription factor glucocorticoid receptor (GR) to the MAGI2-AS3 promoter, resulting in decreased transcriptional activity that subsequently downregulated MAGI2-AS3 expression. Furthermore, functional experiments elucidated that MAGI2-AS3 overexpression suppressed CRC cell proliferation, migration, and invasion capacities, arrested cell cycle at G0/G1 phase, and promoted cell apoptosis.

Conclusion: Taken together, our study demonstrated that the potential function of MAGI2-AS3 as a tumor suppressor for CRC, and the MAGI2-AS3 rs7783388 polymorphism is associated with the increased susceptibility to CRC by altering the binding ability of GR to the MAGI2-AS3 promoter.

Keywords: MAGI2-AS3; colorectal cancer; lncRNA; polymorphisms; rs7783388.