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. 2015 Sep 15;8(9):15852–15856.

MiR-146a rs2910164 polymorphism is associated with hepatocellular carcinoma: a meta-analysis

Jiajun Chen 1,*, Xuedong Cao 1,*, Haiyang Zhang 1
PMCID: PMC4658976  PMID: 26629087

Abstract

Results of published studies on the association between the miR-146a rs2910164 polymorphism and the risk of hepatocellular carcinoma (HCC) were inclusive. We performed a meta-analysis. A literature research was conducted using PubMed, Cochrane Library, Ovid, Embase, Wanfang and China National Knowledge Infrastructure (CNKI) databases, to identify studies. Statistical analyses were conducted in STATA version 11.0 (Stata Corporation, College station, TX, USA). A total of 12 publications were included in this meta-analysis. The results of this meta-analysis suggested that miR-146a rs2910164 was associated with an increased risk of HCC (OR = 1.09, 95% CI = 1.00-1.19). In sensitivity analysis, the result was still positive when excluding the studies without HWE (OR = 1.12, 95% CI = 1.01-1.23). In conclusion, this meta-analysis suggested a significant association between miR-146a rs2910164 polymorphism and HCC risk.

Keywords: Hepatocellular carcinoma, miR-146a, meta-analysis

Introduction

Hepatocellular carcinoma (HCC) accounts for 90% of cases of primary liver cancer and is the fifth most common cancer worldwide. It ranks third in mortality after gastric cancer and esophageal cancer, and half of the deaths from HCC occur in China [1]. Due to the high rate of recurrence or intrahepatic metastasis after curative resection, the overall prognosis of HCC patients remains poor despite obvious improvements in surgical techniques and perioperative management [2]. Accordingly, the development of effective therapeutic targets for HCC is urgently required.

MicroRNAs (miRNAs) are non-coding RNAs formed of 18-25 nucleotides that can cause the inhibition of gene expression at a post-transcriptional level by directly binding to the 3’-untranslational region (UTR) of mRNAs [3]. Deregulation of miRNAs, such as miR-204, miR-331, miR-125b, and miR-146a, has been demonstrated to play an important role in hepatocellular carcinoma [4,5]. Huang et al. found that miR-146a plays a vital role in the cell growth and apoptosis of HCC cells and inducing miR-146a level might be a critical targeted molecular therapy strategy for HCC [6]. Rong et al. suggested that miR-146a expression in HCC tissues was lower compared with that in adjacent non-cancerous hepatic tissues. MiR-146a expression was also related to clinical TNM stage, metastasis, portal vein tumor embolus, and number of tumor nodes [7].

The location of rs2910164 is the stem region opposite to the mature miR-146a sequence, which results in a change from G:U pair to C:U mismatch in the stem structure of the miR-146a precursor. It has previously been shown that SNPs rs2910164 in miR-146a were associated with an increased susceptibility to HCC in an Asian population. However, the results were inconsistent [8-19]. Thus, we did a meta-analysis to assess the association between rs2910164 and the risk of HCC.

Methods

Publication search

A literature research was conducted using PubMed, Cochrane Library, Ovid, Embase, Wanfang and China National Knowledge Infrastructure (CNKI) databases, to identify studies published prior to Jan 2015. Relevant studies were identified using the terms: “miR-146a or MicroRNA-146a” and “polymorphisms or variant” and “hepatocellular carcinoma or HCC”. The search was confined to humans. A manual search of references of the original articles related with this topic was used to identify additional studies. If the data or data subsets were published in more than one paper, only the paper with the largest sample size was enrolled.

Inclusion and exclusion criteria

Studies were selected for meta-analysis if they met the inclusion criteria as follows: (1) case-control study design; (2) studies that investigated the association between the miR-146a rs2910164 and the risk of HCC; (3) study subjects were HCC patients confirmed by histopathology in case group. The exclusion criteria were: (1) reviews and summaries; (2) repetitive publications; (3) no raw data of the miR-146a rs2910164 genotype.

Data extraction

Data from published studies were extracted by two authors. For each study, we collected the following information: first author, year of publication, country, ethnicity, numbers of cases and controls, and evidence of HWE.

Statistical analysis

The overall effect was measured by ORs with its 95% CI. The significance of the pooled ORs was determined by the Z test with a P value less than 0.05 considering statistically significant. The dominant model was examined to assess this association. Between-studies heterogeneity was assessed by the I2 test and the Q-statistic test. A random effects model was applied if there was heterogeneity (P < 0.05 or I2 > 50%), otherwise, a fixed effects model was employed. The publication bias was estimated by visual funnel plot inspection. To assess whether our results were substantially influenced by the presence of any individual study, we proceed a sensitivity analysis by removing the studies without HWE. Statistical analyses were conducted in STATA version 11.0 (Stata Corporation, College station, TX, USA). All the tests were two-sided.

Results

Study characteristics

According to the inclusion and exclusion criteria, a total of 12 publications were included in this meta-analysis. The 12 selected studies contained a total of 4172 HCC patients and 4901 healthy controls. Of the 12 studies, 11 studies were performed in Asians; only 1 study was performed in Caucasians. The sample sizes of the studies varied between 200-1995. Characteristics in this meta-analysis are summarized in Table 1.

Table 1.

Characteristics of included studies

Author Year Country Ethnicity Cases Controls HWE
Xu 2008 China Asian 479 504 Yes
Akkiz 2011 Turkey Caucasian 222 222 Yes
Zhang 2011 China Asian 926 840 Yes
Zhou 2012 China Asian 186 483 Yes
Xiang 2012 China Asian 100 100 Yes
Kim 2012 Korea Asian 159 201 Yes
Zhang 2013 China Asian 997 998 Yes
Shan 2013 China Asian 172 185 No
Kou 2014 China Asian 271 532 No
Chu 2014 China Asian 188 337 Yes
Cong 2014 China Asian 206 218 Yes
Zhou 2014 China Asian 266 281 No
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HWE, Hardy-Weinberg equilibrium.

Results of meta-analysis

Heterogeneity test revealed that no heterogeneity existed under allele and dominant models, and thus a fixed-effect model was used (P = 0.29). The results of this meta-analysis suggested that miR-146a rs2910164 was associated with an increased risk of HCC (OR = 1.09, 95% CI = 1.00-1.19; Figure 1). Subgroup analysis based on ethnicity indicated that the miR-146a rs2910164 increased the risk of HCC in Asian population (OR = 1.09, 95% CI = 1.00-1.19). In sensitivity analysis, the result was still positive when excluding the studies without HWE (OR = 1.12, 95% CI = 1.01-1.23; Figure 2). The funnel plot is symmetrical, suggesting no publication bias (Figure 3). Egger test further verified that no publication bias existed (P = 0.56).

Figure 1.

Figure 1

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Meta-analysis for the association between miR-146a rs2910164 and HCC risk.

Figure 2.

Figure 2

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Sensitive analysis for the association between miR-146a rs2910164 and HCC risk.

Figure 3.

Figure 3

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Funnel plot for the association between miR-146a rs2910164 and HCC risk.

Discussion

In the present study, we found that miR-146a rs2910164 was associated with an increased risk of HCC. In addition, we also noticed that miR-146a rs2910164 increased the risk of HCC in Asian population. However, only one study used Caucasians. Thus, more studies are needed to confirm the result of this meta-analysis.

HCC represents a major form of primary liver malignancy in adults worldwide. The tumorigenesis and development of HCC is typical of a multistage process. Major risk factors for HCC include infection with HBV or HCV, alcoholic liver disease, and most probably nonalcoholic fatty liver disease [20]. The progression is considered to deregulate genes that are critical to biological cellular procedures such as cell cycle control, apoptosis, cell migration, and metastasis [21]. However, the sensitivity and specificity of these markers remain imperfect [22]. Therefore, new biomarkers are needed to help to understand the causes of hepatocarcinogenesis and to predict response possibilities towards different therapeutic methods.

MiR-146a rs2910164 polymorphism which locates in the passenger strand of miR-146a, can disturb the secondary structure and maturation of miR-146a [8]. Xie et al. suggested that digestive tract neoplasms might associate with miR-146a variant [23]. Sun and coworkers indicated that up-regulation of miR-146a expression in tissues was related to carcinogenesis and deterioration of papillary thyroid carcinoma [24].

In conclusion, this meta-analysis suggested a significant association between miR-146a rs2910164 polymorphism and HCC risk.

Disclosure of conflict of interest

None.

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