A functional variant rs353292 in the flanking region of miR-143/145 contributes to the risk of colorectal cancer

Abstract

MicroRNA (miR)-143 and miR-145 have been identified as molecular regulators in cell proliferation, cell growth, clone formation, apoptosis, cell cycle, invasion, and migration. We previously found that rs353292 in the flanking region of miR-143/145 showed a high frequency in patients with colorectal cancer (CRC). To identify whether the rs353292 polymorphism is a risk factor for CRC, we conducted this study with larger samples. A total of 809 patients with CRC and 1005 gender matched controls were collected. The rs353292 polymorphism was genotyped by using TaqMan allelic discrimination. Dual luciferase reporter assay was carried out to measure the transcriptional activity. We found that the rs353292 polymorphism was associated with an increased risk for developing CRC in heterozygous comparison (adjusted OR = 1.70, 95% CI, 1.32–2.20, P < 0.001), dominant genetic model (adjusted OR = 1.62, 95% CI, 1.26–2.09, P < 0.001), and allele comparison (adjusted OR = 1.46, 95% CI, 1.16–1.84, P = 0.001). The rs353292 CT/TT carriers exhibited a lower expression of miR-143 compared to the CC carriers (P = 0.04). Moreover, the pGL3-rs353292T displayed a significantly lower luciferase activity than pGL3-rs353292C (P < 0.01). These findings indicate that the rs353292 polymorphism is functional and may be a risk factor for the development of CRC.

Functional polymorphisms in the promoter region of miR-17-92 cluster are associated with a decreased risk of colorectal cancer

“…Regarding genetic contributions to CRC susceptibility, previous association studies focused on coding genes [ 29 ]. Recently, accumulating epidemiological studies evaluated the association between miRNA related polymorphisms and CRC risk [ 24 - 26 , 30 , 31 ]. Our previous work showed an rs4938723 in the promoter of miR-34b/c having a 0.56-fold decreased risk of CRC [ 24 ].…”

“…The analysis was performed on genomic DNA from 966 CRC cases together with 1154 controls. Detailed information of study population is described in our previous studies [ 30 , 31 ]. In brief, CRC samples were enrolled from the West China Hospital of Sichuan University, the Luoyang Central Hospital Affiliated to Zhengzhou University and the Affiliated Hospital of North Sichuan Medical College between January 2010 and February 2015.…”

The Microrna-143/145 Cluster in Tumors: A Matter of Where and When

“…Li and co-authors first described several SNPs in the regulatory region of the miR-143/145 cluster, several positively correlating with CRC development [64]. The rs353292 variant, which displays reduced transcriptional activity in a Luciferase reporter assay [65], was shown to correlate with lower miR-143, but not miR-145, expression levels and CRC development in tumor samples. Similar findings were reported in the context of the rs4705342T > C and the rs4705343T > C variants, with the T alleles displaying reduced promoter activity and increased prostate cancer or cervical squamous cell carcinoma development [66,67].…”

The Dual Role of MicroRNAs in Colorectal Cancer Progression

“…Dysregulated miR-143-145 clusters may be functionally associated with the pathogenesis of synchronous CRC. Polymorphism rs4705341 and rs353292 in the flanking region of miR-143 and miR-145 was associated with CRC risk and clinical outcome, especially the rs4705341 GG genotype [ 73 , 74 ]. The polymorphisms in the promoter region of these miRNAs were also reported to link with the etiology of CRC [ 75 ].…”