Elsevier

Gene

Volume 533, Issue 1, 1 January 2014, Pages 389-397
Gene

Short communication
Diagnostic and prognostic value of circulating miR-21 for cancer: A systematic review and meta-analysis

https://doi.org/10.1016/j.gene.2013.09.038Get rights and content

Highlights

  • This article is focus on cancer biomarker miR-21 in circulation for clinical practice.

  • This meta-analysis contains both diagnostic and prognostic analyses and systematic reviews.

  • This article included 36 studies from 27 articles.

Abstract

Background

MicroRNAs (miRNAs) have been reported to be aberrantly expressed in patients with cancer. Many studies have shown that circulating miRNAs could play potential roles as diagnostic and prognostic biomarkers of cancers. The aim of this meta-analysis is to summarize the role of circulating miR-21 as a biomarker in patients with a variety of carcinomas.

Material and methods

Eligible studies were identified and assessed for quality through multiple search strategies. For diagnostic meta-analysis, the sensitivity, specificity, and other measures of miR-21 in the diagnosis of cancer were pooled using bivariate random-effects approach models. For prognostic meta-analysis, pooled hazard ratios (HRs) of circulating miR-21 for survival were calculated.

Results

A total of 36 studies dealing with various carcinomas were included for the systemic review. Among them, 23 studies were finally enrolled in the global meta-analysis (17 studies for diagnosis and 6 studies for prognosis). For diagnostic meta-analysis, the overall pooled results for sensitivity, specificity, positive likelihood ratio (LRP), negative likelihood ratios (LRN) and diagnostic odds ratio (DOR) were 75.7% (95% CI: 67.1%–82.6%), 79.3% (95% CI: 74.2%–83.5%), 3.65 (95% CI: 2.83–4.70), 0.31 (95% CI: 0.22–0.43), and 11.88 (95% CI: 6.99–20.19), respectively. For prognostic meta-analysis, the pooled HR of higher miR-21 expression in circulation was 2.37 (95% CI: 1.83–3.06, P < 0.001), which could significantly predict poorer survival in general carcinomas. Importantly, subgroup analysis suggested that higher expression of miR-21 correlated with worse overall survival (OS) significantly in carcinomas of digestion system (HR, 5.77 [95% CI: 2.65–12.52]).

Conclusions

Our findings suggest that circulating miR-21 may not suitable to be a diagnostic biomarker, but it has a prognostic value in patients with cancer.

Introduction

Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries. About 12.7 million new cancer cases and 7.6 million new deaths are estimated to have occurred in 2008 worldwide (Jemal et al., 2011). Most of the cancers are difficult to diagnose because of non-specific clinical presentations, especially in early-stage. Though current diagnostic methods, such as imaging examination and biopsy, have significantly improved accuracy, these methods still have certain limitations as invasive and harmful procedure (Duffy, 2007). Also, we still do not have an effective predictor for prognosis, which could provide important information for clinical treatment. The circulating biomarkers used in current clinical practice are lack of sufficient accuracy. Therefore, it is still a great need to detect simple and reliable biomarker for diagnosing cancers and/or predicting the outcome of cancer patients.

MicroRNAs (miRNAs) are endogenous, small non-coding 18–25 nucleotide RNAs. These miRNAs could be post transcriptional gene regulators that paired to complementary sequences in the 3′ untranslated region (3′ UTR) of target mRNAs, leading to mRNA degradation or translational repression (Bartel, 2004, Bartel and Chen, 2004). These miRNAs could not only regulate gene-expression but also involve in various biogenesis which are associated with carcinogenesis, such as cell proliferation, cell cycle, apoptosis, angiogenesis, invasion, and metastasis (Chen et al., 2012a, Ivanovska et al., 2008, Lu et al., 2007, Takamizawa et al., 2004, Wang et al., 2011a, Wang et al., 2011b).

Evidences from clinical studies suggested that many miRNAs were deregulated in a variety of cancers, and the expression level of some miRNAs correlated with the stage of diseases. Hence, these miRNAs could play potential roles as diagnostic and prognostic biomarkers of cancers (Ferracin et al., 2010, Nana-Sinkam and Croce, 2010). miRNAs especially in circulation, such as serum and plasma, can be non-invasive biomarkers for cancer. Among them, miR-21 was the representative one since it has been extensively studied in various cancers. Many studies showed that the expression level of circulating miR-21 could distinguish cancer patients from healthy people and predict disease outcomes. However, there are inconsistent results for the diagnostic accuracy and the overall risk for prognosis associated with miR-21. Considering the limits of the single study, we conduct this systematic review and meta-analysis to evaluate the diagnostic efficacy and the prognostic significances of cell-free circulating miR-21 in patients with cancer. We also discussed the possibility of cell-free circulating miR-21 as diagnostic and/or prognostic biomarker in clinical practice.

Section snippets

Search strategy

We carefully searched online in PubMed and EMBASE until April 6, 2013 to identify relevant studies. Two distinct sets of key words were used simultaneously, namely ‘circulating/serum/plasma miR-21 and cancer’ and ‘miR-21 and cancer diagnosis or prognosis’. The cited references of retrieved articles were also scanned to identify any additional relevant studies.

Studies were considered eligible if they met the following criteria: (i) they studied the patients with any type of carcinoma; (ii) they

Literature search

528 records for circulating miR-21 and cancer were identified from a primary literature search in PubMed and EMBASE. After manually screening the titles, abstracts and keywords, 474 articles were excluded because they were review articles, letters, non-English articles, laboratory studies, or studies irrelevant to the current analysis. Then we analyzed the remaining 54 articles by reviewing each full text. Twenty-seven articles were omitted because of no cell-free blood sample. The candidate 36

Discussion

Development of suitable biomarkers is critical for diagnosing cancer or predicting patients' outcome. Nowadays, circulating miRNAs attracted much more attention for its high stability and great potential as biomarker. Among the various miRNAs, miR-21 was widely studied and was found aberrantly expressed in various cancers. However, the diagnostic accuracy and prognostic ability was inconsistent or even contradictory in literature.

The present meta-analysis has shown that, as a diagnostic

Conflicts of interest statements

There is no conflict of interest.

Acknowledgments

This manuscript is supported by the National Basic Research Program of China (973program) No. 2012CB9333004 and Clinical Trial Special Fund (11L01).

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