Conflicts of interest br Introduction
Conflicts of interest
Introduction Hepatocellular carcinoma (HCC) is one of the most common cancers and is the second leading cause of cancer death worldwide. In 2012, 782,500 new HCC cases and 745,500 deaths were caused by this persistent disease worldwide, with about 50% of the total number of cases and deaths occurring in China. Currently, HCC is a predominant histological subtype of human liver malignancy, which accounts for 70–85% of primary malignancies in the liver. Hepatitis B virus, hepatitis C virus, obesity, and alcohol abuse lead to HCC, which has been recognized as an insidious malignancy with a very poor prognosis. Unfortunately, most HCC patients enter the late stage when diagnosed and have already missed the window of opportunity to have radical treatments. However, HCC is usually highly malignant and quick to metastasize. Therefore, it is of great importance and benefit for patients with HCC to develop early and noninvasive diagnostic biomarkers. Micro-RNAs (miRNAs) are small, noncoding, single-stranded RNA molecules with a typical length of 22 nucleotides. They also play an important role in physiologic and pathologic processes including cell differentiation, proliferation, apoptosis, and carcinogenesis, and have been implicated in the initiation and progression of various cancers. A miRNA, which has even a slight variation in the function or expression, may affect a wide spectrum of mRNA targets, including many oncogenes and tumor suppressor genes. Single-nucleotide polymorphisms (SNPs) can reportedly alter expressions or functions of miRNAs; related to cancer risk, they are the most common type of genetic variation, which are associated with population diversity, disease susceptibility, and individual response to medicine. Research focusing on both SNPs in miRNAs and human cancer has provided another insight into the molecular mechanisms of cancer development. Recent studies have demonstrated that genetic factors could also contribute to the etiology of HCC. In recent years, we have paid significant attention to genetic polymorphisms due to their etiological roles in defining the risk of HCC development. According to recent research, miR-34b/c, miR-218, miR-146a, miR-149, miR-196a-2, miR-499, and miR106b-25 are related to HCC. A small sample size may not be adequate to detect the effects of SNPs on HCC, so we collected 21 studies for this meta-analysis and explored the associations between polymorphisms of miRNAs and HCC.
Discussion A growing volume of research has shown that miRNAs play an important role in normal development and cellular homeostasis. Therefore, dysfunctions in these molecules have been associated with several human carcinomas, including HCC. Recently, numerous reports have shown that SNPs in miRNAs may not only be involved in the process of HCC, but also contribute to the development of HCC. Therefore, we attempted to search all the eligible studies to show the association between the five SNPs in miRNA Go 6983 [miR-146a G > C (rs2910164), miR-196a-2 C > T (rs11614913), miR-34b/c T>C (rs4938723), miR-499 A > G (rs3746444), and miR-149 (rs2292832)] and susceptibility to HCC. MiR-146a rs2910164 is located in the stem region opposite the mature miR-146a sequence. Owing to the mispairing in the hairpin of the precursor, the mature sequence has altered the process and has lower expression. In other words, the G:U pair to C:U mismatch in the stem structure of miR-146a precursor results in G > C polymorphism. Compared with the G allele, the C allele gene has less efficient inhibition of target genes such as papillary thyroid carcinoma 1 gene and cytokine signaling pathway (tumor necrosis factor receptor-associated factor -6 (TRAF6), interleukin 1 receptor - asspciated kinase 1 (IRAK1)). According to a series of studies, the miR-146a GG genotype could promote colon formation and cell proliferation in HCC cells, in part by having a higher expression level of mature miR-146a. Moreover, the association between miR-146a rs2910164 polymorphism and risks of various cancers has been investigated by several case–control studies, and some believed that miR-146a rs2910164 contributes to modified HCC risks. Our meta-analysis had positive results, as the biological consequence of miR-146a rs2910164 supports a significant association between miR-146a rs2910164 polymorphism and susceptibility to HCC found in the allele, recessive, and homozygous models. In subgroup analysis of the Asian and Caucasian populations, no significant result was shown in Caucasian populations. However, in Asian populations, we found the same association between miR-146a rs2910164 polymorphism and susceptibility to HCC. In several case–control studies, researchers investigated the association between miR-146a rs2910164 polymorphism and the risk of some cancers. Some previous findings showed that there was no association between miR-146a rs2910164 polymorphism and breast cancer, bladder cancer, and nonsmall cell lung cancer. Furthermore, some studies suggested that G allele or GG genotype of miR-146a polymorphism is related to an increased risk of gastric cancer, esophageal cell carcinoma, and prostate cancer. Race differences might be the reason that miR-146a rs2910164 polymorphism has distinct effects, including living habits, genetic background, and the environment, which could be responsible for causing the noted differences. Another rational explanation for the result may be that the allele of miR-146a rs2910164 polymorphism might have a different effect on carcinogenesis in different organs. This phenomenon reflects the diversities of the etiological factors for different cell types. The number of studies used to evaluate the association between miR-146a rs2910164 polymorphism and HCC risk may also lead to the difference that there were 10 studies in Asian populations and only one in Caucasian populations. To further study, deeper insights of biological mechanism, as well as well-designed studies and unbiased larger sample sizes, are needed to elucidate the exact role of miR-146a rs2910164 in HCC susceptibility.