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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 490-493

MiR-499 rs3746444 polymorphism and hepatocellular carcinoma risk: A meta-analysis


Department of Hepato-Biliary- Pancreatic Surgery, Henan Tumor Hospital (The Cancer Hospital Affiliated to Zhengzhou University), Zhengzhou 450008, Henan, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Feng Han
Department of Hepato-Biliary-Pancreatic Surgery, Henan Tumor Hospital (The Cancer Hospital Affiliated to Zhengzhou University), No. 127, Dongming Road, Zhengzhou 450008, Henan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.179090

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 > Abstract 

Aims: Several studies suggested that miR-499 rs3746444 polymorphism was associated with the risk of hepatocellular carcinoma (HCC). However, other studies did not confirm the result. To derive a more comprehensive estimation of the association between miR-499 rs3746444 polymorphism and HCC risk, we conducted a meta-analysis.
Materials and Methods: PUBMED, COCHRANE, and WEB OF SCIENCE databases were retrieved for the association studies focused on the relationship between miR-499 rs3746444 polymorphism and the risk of HCC. The strength of the associations between miR-499 rs3746444 polymorphism and the risk of HCC was measured by odds ratios (ORs) with 95% confidence intervals (CIs).
Results: A statistically significant association between miR-499 rs3746444 polymorphism and the risk of HCC was fond (OR = 1.26; 95% CI, 1.04–1.52; P = 0.02). In the subgroup analysis of race, Asian population with miR-499 rs3746444 polymorphism showed increased HCC risk (OR = 1.29; 95% CI, 1.03–1.62; P = 0.03). In the subgroup analysis of hepatitis virus status, patients with HBV and miR-499 rs3746444 polymorphism showed increased HCC risk (OR = 1.38; 95% CI, 1.17–1.64; P = 0.0002). In the subgroup analysis of source of control, both hospital- and population-based studies found significant results (OR = 1.46; 95% CI, 1.12–1.90; P = 0.005; OR = 1.19; 95% CI, 1.01–1.40; P = 0.04).
Conclusions: This meta-analysis suggested that mir-499 rs3746444 polymorphism was associated with an increased HCC risk.

Keywords: Association, hepatocellular carcinoma, meta-analysis, microRNA


How to cite this article:
Qiu D, Han F, Zhuang H. MiR-499 rs3746444 polymorphism and hepatocellular carcinoma risk: A meta-analysis. J Can Res Ther 2018;14, Suppl S2:490-3

How to cite this URL:
Qiu D, Han F, Zhuang H. MiR-499 rs3746444 polymorphism and hepatocellular carcinoma risk: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2019 Jul 19];14:490-3. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/490/179090


 > Introduction Top


Hepatocellular carcinoma (HCC) is a major global health problem; it has reached to the second leading cause of cancer death in China as reported by the National Central Cancer Registry in 2014.[1] HCC has become the second leading cause of cancer death in China. Importantly, diagnosis in the advanced stages, the paucity of effective therapeutic options, and high rate of tumor recurrence give rise to its high lethality.[2]

MicroRNAs (miRNAs) are small noncoding RNAs, comprising approximately 18–23 nucleotides, which bind to the 3'-untranslated region of messenger RNAs to repress translation or promote degradation.[3],[4],[5] Imperfect base pairing between miRNAs and mRNAs is common and enables miRNAs to regulate a broad, but specific set of genes.[6] Current findings suggest that miRNAs deregulation in cancer is caused by genetic and/or epigenetic, transcriptional, and posttranscriptional modifications resulting in abnormal expression and hallmarks of malignant transformation: Aberrant cell growth, cell death, differentiation, angiogenesis, invasion, and metastasis.[6]

Several studies suggested that miR-499 rs3746444 polymorphism was associated with the risk of HCC. However, other studies did not confirm the result.[7],[8],[9],[10],[11],[12],[13] Therefore, to derive a more comprehensive estimation of the association between miR-499 rs3746444 polymorphism and HCC risk, we conducted a meta-analysis.


 > Materials and Methods Top


Publication search

PUBMED, COCHRANE, and WEB OF SCIENCE databases were retrieved for the association studies focused on the relationship between miR-499 rs3746444 polymorphism and the risk of HCC (the last search update was May 2015). The keywords and subject terms used were as follows: “miRNA 499 or mir-499;” “HCC or HCC or liver cancer;” and “polymorphism or variant.” The research was limited to English-language journals, and the additional studies were identified by a manual search of the reference list from the retrieved studies.

Inclusion and exclusion criteria

The meta-analysis included only articles (i) that evaluated the association of the miR-499 rs3746444 polymorphism and the risk of HCC based on a case–control or cohort design, and (ii) that contained information on the sample sizes, distribution of genotypes, and allele frequencies for the polymorphisms investigated between HCC and non-HCC allowing for calculation of crude risks for HCC. In publications with overlapping cases and/or controls, the most recent or largest population was chosen. In the first step of the analysis, two of the investigators independently identified all studies not meeting any of the prespecified criteria by screening the titles and abstracts, and these studies were excluded. In the second step, the same investigators independently evaluated the full-text publications of the remaining studies. Studies were excluded if they did not meet all of the criteria. Any discrepancies were adjudicated by a third reviewer.

Data extraction

Data were carefully extracted from all eligible publications independently by two investigators, according to the strict criteria for inclusion. Discrepancies would be discussed and adjudicated by a third investigator until consensus was reached on every item. The following data were extracted from each article: The first author's name, year of publication, country of origin, ethnicity, number of cases, controls, genotyped in cases and controls, hepatitis virus status, and source of controls.

Statistical analysis

The strength of the associations between miR-499 rs3746444 polymorphism and the risk of HCC was measured by odds ratios (ORs) with 95% confidence intervals (CIs). Between-study heterogeneity was assessed by Chi-square test and was quantified using the I2 statistic (ranging from 0% to 100%), which was defined as the percentage of the observed between-study variability that is due to heterogeneity rather than chance. When the result of the Q-test and I2 statistics suggested heterogeneity (P ≤ 0.05 and I2 > 50%), a random-effects model (DerSimonian–Laird method) was used; otherwise, fixed-effects model (Mante–Haenszel method) was adopted. To access the stability of the meta-analysis, a cumulative meta-analysis was carried out. Publication bias was assessed by visual inspection of funnel plots, in which the standard error of log (OR) of each study was plotted against its log (OR). The Egger's test was used to assess publication bias statistically. All statistical tests were performed by using STATA 11.0 software (Stata Corporation, College Station, TX, USA). A P < 0.05 was considered significant. All the P values were two-sided.


 > Results Top


Study characteristics

The studies were published from 2011 to 2014, and the sample sizes of cases ranged from 100 to 984. Only one study included Caucasians while other studies included Asians. Three studies reported hepatitis virus status. The characteristics of the selected studies are listed in [Table 1]. Seven studies with 2143 cases and 2809 controls were included in this meta-analysis.
Table 1: Characteristics of studies included in the meta-analysis

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Quantitative data synthesis

As shown in [Figure 1], a statistically significant association between miR-499 rs3746444 polymorphism and the risk of HCC was fond (OR = 1.26; 95% CI, 1.04–1.52; P = 0.02). In the subgroup analysis of race, Asian population with miR-499 rs3746444 polymorphism showed increased HCC risk (OR = 1.29; 95% CI, 1.03–1.62; P = 0.03). In the subgroup analysis of hepatitis virus status, patients with HBV and miR-499 rs3746444 polymorphism showed increased HCC risk (OR = 1.38; 95% CI, 1.17–1.64; P = 0.0002). In the subgroup analysis of source of control, both hospital-based studies and population-based studies found significant results (OR = 1.46; 95% CI, 1.12–1.90; P = 0.005; OR = 1.19; 95% CI, 1.01–1.40; P = 0.04). All the results are shown in [Table 2].
Figure 1: Effect of mir-499 rs3746444 polymorphism and risk of hepatocellular carcinoma

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Table 2: Meta-analysis results and subgroup analyses

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In the sensitivity analysis, the pooled OR did not qualitatively change by omitting a single study at a time [Figure 2]. As shown in [Figure 3], two studies were the outliners and these two studies were considered as the main source of heterogeneity. As illustrated in [Figure 4], funnel plots indicated that there was no evidence of publication bias, and the results of Begg's test also resulted in the same conclusion (P = 0.732).
Figure 2: Sensitivity analysis on the association between mir-499 rs3746444 polymorphism and risk of hepatocellular carcinoma

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Figure 3: Galbraith plot of the association between mir-499 rs3746444 polymorphism and risk of hepatocellular carcinoma

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Figure 4: Funnel plot of publication bias on the association between mir-499 rs3746444 polymorphism and risk of hepatocellular carcinoma

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 > Discussion Top


Many articles have published promising results for miR-499 rs3746444 polymorphism on HCC risk. To clarify the effect of miR-499 rs3746444 polymorphism as a prognostic biomarker, the data from the studies providing independent assessments of miR-499 rs3746444 polymorphism in HCC were systematically evaluated and synthesized. In this meta-analysis, we found a significant association between miR-499 rs3746444 polymorphism and HCC risk. In addition, we found Asians and HBV patients with miR-499 rs3746444 polymorphism had a higher risk of HCC.

miRNAs are key players in a wide array of pathological processes, which may partly explain the prognostic associations in HCC and other cancers. Nikolic et al. suggested that rs3746444 qualifies for a genetic variant potentially associated with prostate cancer aggressiveness in Serbian population.[14] Li et al. indicated that serum miR-499 may prove to be a promising biomarker for early detection and prognosis prediction of nonsmall cell lung cancer.[15] Omrani et al. demonstrated that the hsa-mir-499 rs3746444 polymorphism is associated with higher risk of developing breast cancer in Iranian population.[16] However, the mir-499 rs3746444 polymorphism is not associated with susceptibility to gastric cancer in the Chinese population.[17]

Our study had some advantages. First, heterogeneity analysis and one-way sensitivity analysis were investigated. Second, this meta-analysis included almost all the studies; thus, the statistical power was enough. Third, funnel plots and Egger's tests did not find potential publication bias.

This meta-analysis had some limitations. First, only published studies were included in this meta-analysis, unpublished data, and ongoing studies were not sought, which may have biased our results. Second, a lack of sufficient eligible studies limited the stratified analysis. Third, potential gene-gene interaction and gene-environment interaction were evaluated in this meta-analysis, as no sufficient data could be extracted from the included studies. Fourth, as with most meta-analyses, results should be interpreted with caution because of obvious between-study heterogeneity in some comparisons.


 > Conclusion Top


This meta-analysis suggested that mir-499 rs3746444 polymorphism was associated with an increased HCC risk.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Chen W, Zheng R, Zhang S, Zhao P, Zeng H, Zou X. Report of cancer incidence and mortality in China, 2010. Ann Transl Med 2014;2:61.  Back to cited text no. 1
    
2.
Farazi PA, DePinho RA. The genetic and environmental basis of hepatocellular carcinoma. Discov Med 2006;6:182-6.  Back to cited text no. 2
    
3.
Yan W, Li R, Liu Y, Yang P, Wang Z, Zhang C, et al. MicroRNA expression patterns in the malignant progression of gliomas and a 5-microRNA signature for prognosis. Oncotarget 2014;5:12908-15.  Back to cited text no. 3
    
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Wang J, Chu ES, Chen HY, Man K, Go MY, Huang XR, et al. microRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway. Oncotarget 2015;6:7325-38.  Back to cited text no. 4
    
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Bader AG, Brown D, Stoudemire J, Lammers P. Developing therapeutic microRNAs for cancer. Gene Ther 2011;18:1121-6.  Back to cited text no. 5
    
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Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.  Back to cited text no. 6
    
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Akkiz H, Bayram S, Bekar A, Akgöllü E, Üsküdar O. Genetic variation in the microRNA-499 gene and hepatocellular carcinoma risk in a Turkish population: Lack of any association in a case-control study. Asian Pac J Cancer Prev 2011;12:3107-12.  Back to cited text no. 7
    
8.
Xiang Y, Fan S, Cao J, Huang S, Zhang LP. Association of the microRNA-499 variants with susceptibility to hepatocellular carcinoma in a Chinese population. Mol Biol Rep 2012;39:7019-23.  Back to cited text no. 8
    
9.
Zhou J, Lv R, Song X, Li D, Hu X, Ying B, et al. Association between two genetic variants in miRNA and primary liver cancer risk in the Chinese population. DNA Cell Biol 2012;31:524-30.  Back to cited text no. 9
    
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Zou HZ, Zhao YQ. Positive association between miR-499A>G and hepatocellular carcinoma risk in a Chinese population. Asian Pac J Cancer Prev 2013;14:1769-72.  Back to cited text no. 10
    
11.
Ma Y, Wang R, Zhang J, Li W, Gao C, Liu J, et al. Identification of miR-423 and miR-499 polymorphisms on affecting the risk of hepatocellular carcinoma in a large-scale population. Genet Test Mol Biomarkers 2014;18:516-24.  Back to cited text no. 11
    
12.
Qi JH, Wang J, Chen J, Shen F, Huang JT, Sen S, et al. High-resolution melting analysis reveals genetic polymorphisms in microRNAs confer hepatocellular carcinoma risk in Chinese patients. BMC Cancer 2014;14:643.  Back to cited text no. 12
    
13.
Wang XH, Wang FR, Tang YF, Zou HZ, Zhao YQ. Association of miR-149C>T and miR-499A>G polymorphisms with the risk of hepatocellular carcinoma in the Chinese population. Genet Mol Res 2014;13:5048-54.  Back to cited text no. 13
    
14.
Nikolic Z, Savic Pavicevic D, Vucic N, Cidilko S, Filipovic N, Cerovic S, et al. Assessment of association between genetic variants in microRNA genes hsa-miR-499, hsa-miR-196a2 and hsa-miR-27a and prostate cancer risk in Serbian population. Exp Mol Pathol 2015;99:145-50.  Back to cited text no. 14
    
15.
Li M, Zhang Q, Wu L, Jia C, Shi F, Li S, et al. Serum miR-499 as a novel diagnostic and prognostic biomarker in non-small cell lung cancer. Oncol Rep 2014;31:1961-7.  Back to cited text no. 15
    
16.
Omrani M, Hashemi M, Eskandari-Nasab E, Hasani SS, Mashhadi MA, Arbabi F, et al. hsa-mir-499 rs3746444 gene polymorphism is associated with susceptibility to breast cancer in an Iranian population. Biomark Med 2014;8:259-67.  Back to cited text no. 16
    
17.
Wu XJ, Mi YY, Yang H, Hu AK, Li C, Li XD, et al. Association of the hsa-mir-499 (rs3746444) polymorphisms with gastric cancer risk in the Chinese population. Onkologie 2013;36:573-6.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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