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

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Oncotarget. 2018; 9:5473-5479. https://doi.org/10.18632/oncotarget.16681

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Tiantian Wang, Hao Xu, Ming Qi, Xingsong Tian _ and Xingsong Tian

Abstract

Tiantian Wang1, Hao Xu1, Ming Qi1, Sheng Yan2 and Xingsong Tian1

1 Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China

2 Department of Neurosurgery, The First Hospital Affiliated to Sun Yat-sen University, Guangzhou, Guangdong, China

Correspondence to:

Sheng Yan, email:

Xingsong Tian, email:

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

Received: November 18, 2016 Accepted: March 13, 2017 Published: March 29, 2017

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.


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

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

Flow chart of search strategy

Figure 1: Flow chart of search strategy

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

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).

Quality of selected studies according to QUADAS-2 guidelines.

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

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.

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

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

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.

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

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

Conflicts of interest

The author declares no conflicts of interest.

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