Abstract
BackgroundVariant in pri-miRNA could affect miRNA expression and mature process or splicing efficiency, thus altering the hereditary susceptibility and prognosis of cancer. We aimed to assess miRNA-let-7 single nucleotide polymorphisms (SNP) associated with the risk and prognosis of gastric cancer (GC) as predicting biomarkers, and furthermore, its possible mechanisms.MethodsA two-stage case-control study was designed to screen four miRNA SNPs (pri-let-7a-2 rs629367 and rs1143770, pri-let-7a-1 rs10739971, pri-let-7f-2 rs17276588) in 107 GC patients, 107 atrophic gastritis (AG), and matched 124 controls using PCR-RFLP. Two promising SNPs were validated in another independent 1949 samples (including 579 gastric cancer patients, 649 atrophic gastritis and 721 controls) using Sequenom MassARRAY platform and sequencing.ResultsWe found that pri-let-7a-2 rs629367 CC variant genotype was associated with increased risks of gastric cancer and atrophic gastritis by 1.83-fold and 1.86-fold, respectively. For gastric cancer prognosis, patients with rs629367 CC genotype had significantly poorer survival than patients with AA genotype (log-rank P = 0.004). We further investigated the let-7a expression levels in serum and found that let-7a expression elevated gradually for rs629367 AA, CA, CC genotype in the atrophic gastritis group (P = 0.043). Furthermore, we confirmed these findings in vitro study by overexpressing let-7a carrying pri-let-7a-2 wild-type A or polymorphic-type C allele (P<0.001).Conclusionspri-let-7a-2 rs629367 CC genotype could increase the risks of gastric cancer as well as atrophic gastritis and was also associated with poor survival of gastric cancer, which possibly by affecting the mature let-7a expression, and could serve as a predicting biomarker for high-risk and poor prognosis of gastric cancer.
Highlights
MicroRNAs are 18–25 nucleotide-long, singlestranded noncoding RNA [1]
Main effect of miRNA polymorphisms on gastric cancer and atrophic gastritis risk The genotype frequencies of the studied single nucleotide polymorphisms (SNP) in the screening stage were shown in Table 1 and the electrophoretogram and sequencing figure of these four miRNA polymorphisms genotypes were shown in Supplementary Figure S1. pri-let-7f-2 rs17276588 was excluded from further analysis because it deviated from Hardy–Weinberg equilibrium (HWE)
When compared with the common AA genotype, the variant CC genotype was associated with a 1.83-fold increased risk of gastric cancer (P = 0.048, 95%CI = 1.01–3.32,Table 1), and was associated with a 1.86-fold increased risk of atrophic gastritis (P = 0.032, 95%CI = 1.06–3.28, Table 1)
Summary
MicroRNAs (miRNAs) are 18–25 nucleotide (nt)-long, singlestranded noncoding RNA [1]. Any variation in pri-miRNA, premiRNA or mature miRNA may affect the mature process and function of miRNA, which could further affect the expression of hundreds of proteins in the interaction pathway [2]. The pri-miRNA of let-7 family could combine with LIN28 and suppress the splicing procedure of Drosha and Dicer, two important restriction enzymes involving in the mature process for all miRNA [7]. By knocking down the Drosha enzyme to suppress all the miRNA mature process comprehensively, Kumar at al found that the main reason for the activation and promotion of cell’s malignant transformation was the downregulation of let-7 family expression [8]. Variant in pri-miRNA could affect miRNA expression and mature process or splicing efficiency, altering the hereditary susceptibility and prognosis of cancer. We aimed to assess miRNA-let-7 single nucleotide polymorphisms (SNP) associated with the risk and prognosis of gastric cancer (GC) as predicting biomarkers, and its possible mechanisms
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