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Review
. 2016 Dec 6;7(49):81621-81633.
doi: 10.18632/oncotarget.13154.

miRNA-200a/c as potential biomarker in epithelial ovarian cancer (EOC): evidence based on miRNA meta-signature and clinical investigations

Yue Teng  1 , Xuan Su  2 , Xing Zhang  3 , Yan Zhang  4 , Chen Li  1 , Wenquan Niu  5 , Chang Liu  3 , Kai Qu  3
Affiliations
Review

miRNA-200a/c as potential biomarker in epithelial ovarian cancer (EOC): evidence based on miRNA meta-signature and clinical investigations

Yue Teng et al. Oncotarget. .

Abstract

Extensive effort has been put on miRNA expression signatures in epithelial ovarian cancer (EOC). Unfortunately, consistent conclusion rarely yielded from diverse studies, mainly due to the high inter-lab variability and small sample sizes. To overcome above limitations, an integrated analysis of miRNA expression signature was performed by employing Robust Rank Aggregation (RRA) method. Diagnostic analysis, Kaplan-Meier survival curves and pathway enrichment analysis were used to investigate the clinical values and biological functions of meta-signature miRNAs. A total of 519 EOC and 248 noncancerous samples were included. Seven mostly dysregulated miRNAs were identified by RRA method and two miRNAs (miR-200a-3p and miR-200c-3p) remained statistically significant after Bonferroni-correction. Diagnostic meta-analysis showed reliable diagnostic capacity of miR-200a-3p (with a pooled sensitivity of 0.84 and specificity of 0.83) and miR-200c-3p (with a pooled sensitivity of 0.75 and specificity of 0.66) for EOC. Pathway enrichment analysis and expression correlation analysis suggested miR-200a/c might contribute EOC progression by affecting cellular adhesion process. Kaplan-Meier survival analysis based on two independent cohorts revealed a strong association between miR-200a/c and overall survival in EOC patients. miR-200a/c was identified as the mostly dysregulated miRNAs in EOC and might be novel diagnostic and prognostic biomarkers for patients with EOC.

Keywords: Robust Rank Aggregation; epithelial ovarian cancer (EOC); miRNA-200a/c.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare they have no potential conflicts of interest.

Figures

Figure 1
Figure 1. Distribution of miRNA alterations in EOC as reported in 14 primary miRNA profiling datasets
Short red and blue vertical bars indicated upregulated and downregulated miRNAs, respectively. miRNAs are aligned according to miRBase release 21. The number of miRNAs in each study is graphically depicted on the left. The positions of EOC integrated-signature miRNAs have been marked.
Figure 2
Figure 2. Ranks for miR-200a-3p and miR-200c-3p in 14 primary miRNA profiling datasets
The ranks for miR-200a-3p and miR-200c-3p in each of the enrolled study were depicted. Each column represents one of the 14 primary miRNA profiling datasets. The rank of miRNAs in each study is graphically depicted on the left.
Figure 3
Figure 3. Forest plots showing the sensitivity and specificity of miR-200a/c in the diagnosis of EOC
A. Forest plot showing the sensitivity of miR-200a-3p in the diagnosis of EOC. B. Forest plot showing the specificity of miR-200a-3p in the diagnosis of EOC. C. Forest plot showing the sensitivity of miR-200c-3p in the diagnosis of EOC. D. Forest plot showing the specificity of miR-200c-3p in the diagnosis of EOC. 95%CI: 95% of confidence interval; EOC: epithelial ovarian cancer.
Figure 4
Figure 4. Summary receiver operating characteristic (SROC) curve of miR-200a/c in the diagnosis of EOC
A. Summary receiver operating characteristic (SROC) curve of miR-200a-3p in the diagnosis of EOC. B. Summary receiver operating characteristic (SROC) curve of miR-200c-3p in the diagnosis of EOC. AUC: area under curve; SROC curve, summary receiver operator curve; SENS: sensitivity; SPEC: specificity; EOC: epithelial ovarian cancer.
Figure 5
Figure 5. miR-200a/c target prediction and pathway enrichment analysis
A. The top 15 saturated pathways affected by miR-200a/c. B. Heatmap of the pathway enrichment of validated miR-200a/c target genes. Rows: pathways; Columns: genes. Range of colors (deep red to white) shows the range of expression values (high to low). C. Schematic of pathway prediction results by web tools including DAVID + GeneCodis algorithms and DIANA mirpath algorithm.
Figure 6
Figure 6. Correlation of miR-200a/c with cellular adhesion-related genes
A. Schematic of Pearson's correlation of miR-200a/c with cellular adhesion-related genes. Genes with an r2 >0.1 were shown as red dots. B. Pearson's correlation of miR-200a/c with cellular adhesion-related genes. The r2 and P values for each of the top 9 genes were demonstrated for miR-200a and miR-200c. C. Kaplan–Meier analysis of overall survival for patients with different miR-200a/c expression levels. Data were drawn from two independent cohort studies (HiSeq-TCGA and GSE27290). The red lines represent the high risk groups, and the green lines represent the low risk groups.
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