Research on the impact of single nucleotide polymorphisms (SNPs) on the occurrence and development of diseases has increased over the years. With the development of molecular biology, discussions on genetic problems have become necessary. In the face of multiple pathogenic factors such as: HPV infection, risky living environment, and host factors; which together lead to the occurrence of cervical cancer, while studying this process in depth, we found that the microenvironment formed by the regulation of certain genes in the human body seems to guide the occurrence of cervical cancer[26, 27, 28].
MiRNAs regulate gene expression at the post-transcriptional level, participate in the regulation of various cellular functions. They affect cell proliferation, apoptosis and carcinogenesis. Variation of a certain miRNA, such as the conversion, insertion, deletion or mismatch of a single base, can cause the polymorphism of the whole DNA sequence. This may in turn affect the function of cells and tissues and the whole host microenvironment. Therefore, miRNAs may be used to predict the occurrence and development of cervical cancer. We selected three kinds of miRNA polymorphisms (miRNA-146a rs2910164, miRNA-499 rs3746444 and miRNA-196a2 rs11614913), that have been studied more frequently in order to analyze their relationship with susceptibility to cervical cancer[16–23].The results showed that, the polymorphisms of miRNA-146a rs2910164 (mutant C allele) and miRNA-196a2 rs11614913 (mutant T allele) significantly reduced the risk of cervical cancer. There was no significant correlation between the polymorphisms of miRNA-499 rs3746444 and cervical cancer.
In the study using PCR-RFLP analysis, the polymorphism of miRNA-146a rs2910164 significantly reduced the risk of cervical cancer in homozygote, heterozygote, dominant, recessive, allele models. With regard to the TaqMan analysis of the genotypes, the polymorphism of miRNA-196a2 rs11614913 significantly reduced the risk of cervical cancer in homozygous, recessive, and allelic models. According to the Chinese studies, miRNA-196a2 rs11614913 reduced cervical cancer risk in homozygous, recessive and allelic models, whereas in Indian studies, it significantly reduced cervical cancer risk in homozygous, dominant, recessive and allelic models. Thus, using different genotype analysis methods and in different countries, the correlation between the polymorphisms of miRNA-146a rs2910164 and miRNA-196a2 rs11614913 and cervical cancer is somehow different. However, it cannot be denied that they can both reduce the risk of cervical cancer.
Meanwhile, a study by Yan et al showed that the mutant T allele in the miRNA-126 rs4636297 polymorphism was associated with cervical cancer susceptibility, and the mutant T gene increased cervical cancer susceptibility compared to the wild C gene. Wang et al reported that the mutant C allele in the polymorphism of miRNA-149 rs2292832 was associated with cervical cancer susceptibility, and the mutant C gene increased cervical cancer susceptibility relative to the original T gene. Furthermore, Chuntao noted that mutation of A allele to G allele in the polymorphism of miRNA-30c rs928508 could reduce the susceptibility to cervical cancer. Fu K showed that miRNA-125 can negatively regulate the expression of VEGF in cervical cancer tissues and inhibit the PI3K/AKT signaling pathway to inhibit cell proliferation, invasion and metastasis in cervical cancer, thus preventing the progression of cervical cancer . The study of Lu X showed that miRNA-186-3p could inhibit the proliferation and migration of cervical cancer cell lines by inhibiting the expression of IGF1, and induce the apoptosis rate of cervical cancer cells . The above studies all indicate that miRNA expression is closely related to the occurrence and development of cervical cancer. However, due to few studies on the related miRNA polymorphisms, they were not included in the meta-analysis. These loci may present more in-depth studies in the future.
Persistent infection with high-risk HPV is a major factor in the development of cervical cancer[33, 34]. However, the occurrence of cervical cancer is a multigene, multistage abnormal regulation process[35, 36]. Studies have also shown that the abnormal expression of miRNAs affects the cervical epithelial cell carcinogenesis[37, 38]. Different miRNAs regulate different biological activities; some target to regulate the activity of tumor suppressor genes to inhibit development of the cancer cells. Others accelerate the growth and metastasis of cancer cells by stimulating proto-oncogenes and metastasis genes. Studies have shown that the polymorphism of miRNA-146a rs2910164 G to C leads to increased expression of miR-146a, and the mutant CC genotype is associated with reduced risk of cervical cancer. As a mediator of the pro-apoptotic transcription nuclear factor kappaB, miRNA-146a affects apoptosis and hence influences the development of cancer. Each cancer tissue has its specific miRNA target, so the miRNA-146a polymorphism may affect the occurrence and development of cervical cancer through certain pathways. MiRNA-196a2 rs11614913 is a polymorphic site in the mature miR-196a2 sequence, and its mutation expression in situ gene C, the T allele, was found to be associated with reduced risk of cervical cancer. Studies have shown that C gene increases the expression of mature miR-196a2 in cervical cancer patients, and this overexpression changes the state of binding of miR-196a2 to its target genes, thereby affecting the development of cervical cancer.Tracking the changes of the two genetic polymorphism loci in human may help to understand how to reduce the incidence of cervical cancer, by changing the internal human environment. Therefore, these two sites may become the targets for the prevention and treatment of cervical cancer in the future.
However, this meta-analysis had several limitations: (1) Due to the fewer factors controlled by relevant studies, the relationship between age, number of abortions and the expression of the three miRNAs in cervical cancer patients was not analyzed. (2) Heterogeneity in some polymorphisms could have arose from different types of cervical cancer and other factors associated with the participants themselves. (3) This meta-analysis did not establish whether the mixed effects of genetic polymorphisms were associated with susceptibility to cervical cancer.