The SNP rs4846048 of MTHFR enhances the cervical cancer risk through association with miR‐522: A preliminary report

Abstract

Background The present research was designed to explore the association between single nucleotide polymorphisms (SNPs) at the 3′‐untranslated region (3′‐UTR) of methylenetetrahydrofolate reductase (MTHFR) and the risk of cervical cancer (CC). Methods From May 2015 to October 2016, a total of 197 patients (diagnosed with CC and precancerous lesions, and underwent surgical treatments) were enrolled in the study. Meanwhile, a total of 80 healthy cases were used as the controls. PCR‐DNA analysis was used to explore the genotype of the SNPs (rs4846048 and rs55763075) of the MTHFR 3′‐UTR as well as the association between allelic frequencies and the CC risk. Then, the role of rs4846048 SNPs in the association of microRNA‐522 (miR‐522) and MTHFR was evaluated through luciferase reporter assay. Meanwhile, the modulatory influence of miR‐522 on cell apoptosis and viability of Hela cells was also detected by flow cytometry and MTT assay. Results The rs4846048 AG and G allele frequencies were significantly higher in CC subgroup compared with the control group. Methylenetetrahydrofolate reductase rs4846048 A/G alleles contributed to miR‐522 binding, and miR‐522 negatively modulated the expressions of MTHFR. Furthermore, miR‐522 overexpression increased cell viability but decreased apoptotic cells in Hela cells. Conclusion The preliminary report revealed that the SNP rs4846048 of MTHFR enhanced the risk of CC through association with miR‐522, which further regulated cell viability and apoptosis in Hela cells.

Association analysis of maternal MTHFR gene polymorphisms and the occurrence of congenital heart disease in offspring

“…A cancer study found that mir-22-3p inhibited MTHFR expression when folic acid was deficient [ 47 ]. The latest preliminary report pointed out that the genetic polymorphism of MTHFR gene at rs4846048increased the risk of cervical cancer through its association with miR-522 [ 48 ]. Interestingly, we found that the offspring of mothers carrying the haplotype G–C (involving rs4846048 and rs2274976) had an increased risk of CHD (OR = 1.31).…”

A Functional Variant rs2072915 is Associated with the Susceptibility and Mortality of Cervical Squamous Cell Carcinoma

“… 14 The rs4846048 G allele in the 3ʹ-UTR of methylenetetrahydrofolate reductase was associated with an increased risk of cervical cancer by enhancing the binding ability to miR-522. 16 Through up-regulating the expression of caspase-3, the rs1049216 TT genotype in the miR-181a binding site conferred not only a significantly decreased risk but also the progression of cervical cancer. 15 These findings provide a clue that genetic polymorphisms in the miRNA-target binding sites may be related to the susceptibility of cervical cancer.…”

“…[7][8][9][10][11] Currently, several susceptibility factors of cervical cancer have been discovered, such as single nucleotide polymorphisms (SNPs) in the binding sites of miRNAs. [12][13][14][15][16] The SNPs may affect miRNAs binding, alter the expression of miRNAs target genes, and finally modify the risk of CSCC. 15,16 Moreover, genome wide association studies (GWAS) have identified 6p21.32 as a susceptibility locus of cervical cancer.…”

“…[12][13][14][15][16] The SNPs may affect miRNAs binding, alter the expression of miRNAs target genes, and finally modify the risk of CSCC. 15,16 Moreover, genome wide association studies (GWAS) have identified 6p21.32 as a susceptibility locus of cervical cancer. 17,18 After searching the region of 6p21.32 with an online database software, 19 we found an SNP rs2072915 that is located in the 3ʹ-UTR of retinoid X receptor beta (RXRB) with a binding site of miR-637.…”

Associations of the <em>MTHFR</em> rs1801133 polymorphism with gastric cancer risk in the Chinese Han population

“…In particular, genetic polymorphisms in the MTHFR gene are associated with colorectal cancer risk (12,13). A previous study found that rs4846048 increased the risk of colorectal cancer through its association with miR-522, and further regulated the survival and apoptosis of HeLa cells (14). Additionally, rs1801131 is associated with an increased risk of gastrointestinal toxicity (15), and the rs1801131-CC genotype is associated with sporadic breast cancer (16).…”