Abstract
Single-nucleotide polymorphisms (SNPs) in microRNA machinery genes might affect microRNA processing and subsequently impact tumorigenesis. The aim of this study was to investigate the associations between SNPs in microRNA machinery genes and hepatocellular carcinoma (HCC) in a Korean population. Genotyping of six SNPs in microRNA machinery genes was performed using blood samples from 147 patients with HCC and 209 healthy control subjects. None of the six SNPs in microRNA machinery genes were significantly associated with HCC development. However, among the models for six polymorphic loci—DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), RAN (rs14035) and XPO5 (rs11077)—one allele combination (A-A-T-C-C-C) showed synergistic effects in terms of an increased risk of HCC development (odds ratio = 8.881, 95% confidence interval [CI] = 1.889–41.750; P = 0.002). Multivariate Cox proportional hazard regression analysis showed a significant survival benefit for the DICER rs3742330 GG compared with the AA type (hazard ratio [HR], 0.314; 95% CI, 0.135–0.730; P = 0.007) and for the RAN rs14035 CT compared with the CC genotype (HR, 0.587; 95% CI, 0.349–0.987; P = 0.044). Although we found no direct association between DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), RAN (rs14035) or XPO5 (rs11077) polymorphisms and HCC risk, we demonstrated that DICER (rs3742330) and RAN (rs14035) were associated with the survival of HCC patients. Future studies with larger samples are needed to determine associations of SNPs in microRNA machinery genes with HCC risk and prognosis.
Highlights
Several studies have demonstrated the association between key genes of the microRNA biosynthetic pathway and the development of various cancer, including Hepatocellular carcinoma (HCC). [6,7,8,9] For example, microRNA machinery genes including DICER, DGCR8, AGO3, and AGO4 were found to be dysregulated in HCC
[10] Altered expression of DICER was associated with the development of lung and prostate cancers. [11,12,13] Taken together, these emerging lines of evidence suggest that microRNA machinery genes play important roles in cancer development and progression
Survival of patients with HCC was associated with TNM stage, Child-Pugh class, portal vein thrombosis, surgical resection, chemotherapy or radiotherapy, DICER rs3742330 GG genotype, and RAN rs14035 CT genotype. We performed this case-control study to evaluate the associations of DICER, DROSHA, RAN and XPO5 polymorphisms with HCC
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. [1] HCC is caused by hepatitis B and C viruses, smoking, alcohol consumption, chemical exposure, aflatoxin B1, and intrinsic factors such as geneticPLOS ONE | DOI:10.1371/journal.pone.0162279 September 9, 2016MicroRNA Machinery Genes and Hepatocellular Carcinomamutations. [2] the mechanisms of how these risk factors affect the susceptibility and severity of HCC remains unclear.MicroRNAs are short, non-coding RNAs of approximately ~23 nucleotides that act as posttranscriptional regulators of gene expression and have been implicated in the initiation and progression of various cancers. [3] In microRNA processing, DROSHA and its cofactor, DGCR8 process primary microRNAs into precursor-microRNAs (pre-microRNAs). Several studies have demonstrated the association between key genes of the microRNA biosynthetic pathway and the development of various cancer, including HCC. [14,15] The important role played by microRNAs in cancer [16] suggests that SNPs in microRNA machinery genes might affect microRNA processing and subsequently impact tumorigenesis. Recent studies have demonstrated an association between SNPs in microRNA machinery genes and the risk of several cancers through affecting the mature process of microRNAs. [16] to date, few studies have investigated the association between SNPs in microRNA machinery genes and HCC development and survival. In the present study, we determined whether polymorphisms in DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), RAN (rs14035) and XPO5 (rs11077) were associated with HCC development and survival in a Korean population
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