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. 2017 Mar 29;9(4):5473–5479. doi: 10.18632/oncotarget.16681

miRNA dysregulation and the risk of metastasis and invasion in papillary thyroid cancer: a systematic review and meta-analysis

Tiantian Wang 1, Hao Xu 1, Ming Qi 1, Sheng Yan 2, Xingsong Tian 1
PMCID: PMC5797065  PMID: 29435194

Abstract

Thyroid cancer (TC) is the most common endocrine malignancy, with an incidence continuing to grow every year. Although thyroid cancer as a whole is generally indolent and relatively easy to treat, some subtypes carry a higher rate of metastasis and cancer-related mortality. A growing number of studies have focused on the dysregulation of miRNAs in TC. However, differences in methods make comparison of gene profiling data difficult. A meta-analysis of published studies comparing miRNA expression data of invasive thyroid carcinoma with paired non-invasive tumors or normal tissues was performed by searching the literature for “invasion”, “thyroid cancer”, and “miRNA”. This revealed 29 dysregulated miRNAs associated with TC in 16 articles; the presence of invasion was confirmed in each respective article by laboratory research or patient follow-up. Among these miRNAs, miRNA-146b, miRNA-221, and miRNA-222 were analyzed further due to their higher frequencies across multiple studies. Of these studies, 6 were included in the meta-analysis, as they compared invasive PTC with paired normal tissues or non-invasive PTC.

Keywords: miRNA, invasive thyroid cancer, metastasis, meta-analysis

INTRODUCTION

Thyroid carcinoma (TC) is the most common endocrine malignancy, the incidence was increasing year by year. Papillary thyroid cancer(PTC) takes up more than 80% of TC. The overall survival rate of patients with papillary thyroid carcinoma is high [1], however, increased cancer recurrence and cancer-related mortality are noted in a portion of patients with papillary thyroid carcinoma [2]. Distinguishing these tumors from classic tumors has therefore become a hot topic of research in recent years.

MicroRNAs (miRNAs) are a recently identified class of small, endogenous, non-coding RNAs that act as negative regulators of gene expression [3]. miRNAs are abundant and ubiquitous, and impact almost all fundamental cell processes such as growth, differentiation, apoptosis, and adhesion [4]. Dysregulation of miRNA expression is a common feature in many types of human cancers, including thyroid cancer [5 6].

RESULTS

Study collection and inclusion

We initially collected 106 studies using the described strategy. 84 articles were excluded because they were not relevant to the aim of our study. 29 miRNAs in 16 articles were subsequently identified [7-23], with the function of dysregulated miRNAs confirmed through patient follow-up or other laboratory experiments. The dysregulated miRNAs are shown in detail in Tables 1a-1b.

Table 1a. Studies demonstrating an association between upregulated miRNAs and invasion.

miRNA Author Year Country Method
MiRNA-146b Chou 2010 China qRT-PCR
Chou 2012 China qRT-PCR
Deng 2015 China qRT-PCR
Lee 2013 Australia Micro array
Lima 2016 Brazil qRT-PCR
Yang 2013 China Micro array
Wang 2013 China Micro array
MiRNA-222 Chou 2010 China qRT-PCR
Lee 2013 Australia Micro array
Jikuzono 2013 Africa qRT-PCR
Yang 2013 China Micro array
Chou 2012 China qRT-PCR
Wang 2013 China Micro array
MiRNA-221 Chou 2010 China qRT-PCR
Chou 2012 China qRT-PCR
Jikuzono 2013 Africa qRT-PCR
Wang 2013 China Micro array
Zhou 2012 China Northern blot
Yang 2013 China Micro array
MiRNA-4295 Shao 2015 China Micro array
MiRNA-101 Wang 2014 China qRT-PCR
MiRNA-183 Wei 2015 China qRT-PCR
MiRNA-210 Yang 2013 China Micro array
MiRNA-584 Xiang 2015 China qRT-PCR
MiRNA-1244 Yang 2013 China Micro array
MiRNA-134 Yang 2013 China Micro array
MiRNA-214 Yang 2013 China Micro array
MiRNA-1202 Wang 2013 China Micro array
MiRNA-193 Wang 2013 China Micro array
MiRNA-2861 Wang 2013 China Micro array
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Table 1b. Studies demonstrating an association between downregulated miRNAs and invasion.

MiRNA Author Year Country Method
MiRNA-539 GU 2015 China qRT-PCR
MiRNA-144 Guan 2014 China qRT-PCR
MiRNA-7 Hua 2016 China Micro array
Wang 2013 China Micro array
MiRNA-182 Zhu 2014 China Micro array
MiRNA-126 Xiong 2015 USA qRT-PCR
MiRNA-486 Yang 2013 China Micro array
MiRNA-206 Zhang 2015 China Micro array
MiRNA-1302 Yang 2013 China Micro array
MiRNA-1231 Yang 2013 China Micro array
MiRNA-637 Yang 2013 China Micro array
MiRNA-1826 Yang 2013 China Micro array
MiRNA-1225 Yang 2013 China Micro array
MiRNA-564 Wang 2013 China Micro array
MiRNA-664 Wang 2013 China Micro array
MiRNA-542 Wang 2013 China Micro array
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miRNA inclusion

Among these miRNAs, miRNA-146b, miRNA-221, and miRNA-222 were analyzed further due to their appearance at higher frequency. Of the studies that analyzed these miRNAs, 6 were selected for meta-analysis because they compared invasive PTC with paired normal tissues or non-invasive PTC [7-12]. These dysregulated miRNAs are shown in detail in Table 2.

Table 2. Studies included in the meta-analysis.

MiRNA Author Year Country Methods Samples (tumor/control)
MiRNA-146b Chou 2010 China qRT-PCR 16/16
Chou 2012 China qRT-PCR 30/41
Deng 2015 China qRT-PCR 30/30
Lee 2013 Australia Micro array 9/17
Yang 2013 China Micro array 3/3
Wang 2013 China Micro array 3/3
MiRNA-221 Chou 2010 China qRT-PCR 16/16
Chou 2012 China qRT-PCR 30/41
Lee 2013 Australia Micro array 9/17
Yang 2013 China Micro array 3/3
MiRNA-222 Chou 2010 China qRT-PCR 16/16
Chou 2012 China qRT-PCR 30/41
Lee 2013 Australia Micro array 9/17
Yang 2013 China Micro array 3/3
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Data characteristics

The 6 included articles are shown in Table 2. In all, 201 samples were analyzed, including 91 invasive tumors and 110 paired control tissues (either non-invasive tumors or normal tissue).

Meta-analysis results

miRNA-146b was upregulated in all 6 studies, while miRNA-221 and miRNA-222 were upregulated in 4 studies. The forest plot is shown in Figure 3. Given that I2 > 50%, the fixed-effects model was used. p < 0.00001 for each miRNA was determined, suggesting that miRNA-146b, miRNA-221, and miRNA 222 are all upregulated in invasive tumors compared with paired control.

Figure 3. Forest plots for miRNA-146, miRNA-221, and miRNA-222 in the described articles.

Figure 3

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As I2 > 50%, a random-effects model was used. p < 0.05, indicated that miRNA-146, miRNA-221, and miRNA-222 were all upregulated in invasive tumors compared with paired controls.

Figure 1. Flow chart of search strategy.

Figure 1

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Figure 2. Quality of selected studies according to QUADAS-2 guidelines.

Figure 2

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Publication bias

Publication bias in our study was assessed using funnel plot analysis. As shown in Figure 4, there was minimal publication bias in this research, though some amount is unavoidable due to the lack of prior research.

Figure 4. Funnel plot to measure publication bias, with regards to miRNA-146.

Figure 4

Figure 4

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Due to the relative lack of research studies, publication bias is somewhat unavoidable.

DISCUSSION

Thyroid carcinoma (TC) is the most common endocrine malignancy. The overall survival rate of patients with thyroid carcinoma is high [1], however, increased cancer recurrence and cancer-related mortality are noted in a portion of patients with papillary thyroid carcinoma [2]. Distinguishing these tumors from classic non-lethal papillary tumors has therefore become a hot topic of research in recent years.

MicroRNAs (miRNAs) are a recently identified class of small, endogenous, non-coding RNAs that act as negative regulators of gene expression [3]. miRNAs are abundant and ubiquitous, and they impact almost all fundamental cell processes including growth, differentiation, apoptosis, and adhesion [4]. Dysregulation of miRNA expression is a common feature of many types of human cancers, including thyroid cancer [5 6].

It is well-known that many dysregulated miRNAs contribute to the tumorigenesis and progression of tumors. Many studies show a direct relationship between dysregulated miRNAs and the molecular mechanisms they induce to affect tumor invasion, but there has been less research addressing the clinical features surrounding invasion ability. In this article, we explored the relationship between dysregulated miRNAs and invasion ability. We searched the PubMed online database using the keywords “papillary thyroid carcinoma” or “thyroid carcinoma”, “miRNA”, and “invasion” and collected 106 records following the strategy described above. 84 articles were excluded because they were not relevant to the aim of our study. 29 miRNAs in 16 articles were identified with the function of the dysregulated miRNAs confirmed via patient follow-up or other laboratory experiments. Among these miRNAs, miRNA-146b, miRNA-221, and miRNA-222 were analyzed further. In total, 6 studies were included in the meta-analysis because they compared invasive PTC with paired normal tissues or non-invasive PTC.

The present meta-analysis has several limitations. Firstly, due to the lack of significant current research, only 6 articles comparing invasive PTC with paired non-invasive PTC or normal tissues were able to be included. Secondly, the divergence of incorporated studies also likely contributed to the statistical differences. Finally, there was a lack of strong correlation between overall patient survival statistics and the presence of dysregulated miRNAs due to lack of patient follow-up.

MATERIALS AND METHODS

Search strategy

A search for dysregulated miRNAs in papillary thyroid carcinoma was performed by querying the PubMed online database with the terms “miRNA” or “microRNA” or “miR”, “thyroid carcinoma” or “papillary thyroid carcinoma”, and “invasion”. Titles and abstracts of the obtained articles were screened, and full texts of the articles of interest were further evaluated.

Inclusion and exclusion criteria

Research studies were considered to be eligible if they met the following criteria: (1) the study focused on patients with any type of papillary thyroid carcinoma; (2) the effect of the dysregulated miRNA on invasion was confirmed via analysis of the patients’ metastases or other experimental tests in the same article; (3) for meta-analysis articles, miRNA effect was confirmed through patient follow-up. Articles were excluded based on the following criteria: (1) reviews, letters, comments, or pure laboratory studies; (2) absence of specific evidence showing the dysregulated miRNA had any influence on invasion; (3) discrepant conclusions across different articles.

Statistical analysis

The fixed-effects and random-effects models were used for the meta-analysis according to heterogeneity among the pooled studies. The heterogeneity test for the pooled odds ratio (OR) was verified using the I2 statistic. A random-effects model was applied if the heterogeneity was significant (p < 0.01 or I2 > 50%), while a fixed-effects model was applied if the heterogeneity was not significant (p > 0.01 or I2 < 50%). Publication bias was estimated using a funnel plot. All p values were calculated using a two-sided test; differences were considered statistically significant when p < 0.05. All statistical analyses were conducted using the Review Manager 5 (Cochrane Tech, London, UK) and Microsoft Excel (Microsoft Corporation, Seattle, WA, USA) software.

CONCLUSIONS

Current evidence and the findings of this article suggest, despite the limitations described above, that dysregulation of these miRNAs leads to increased invasion ability of thyroid carcinoma.

Footnotes

CONFLICTS OF INTEREST

The author declares no conflicts of interest.

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