Integrative data mining and meta-analysis to investigate the prognostic role of microRNA-200 family in various human malignant neoplasms: A consideration on heterogeneity

Background: Existing meta-analysis have shown that the miR-200 family can be taken as a prognostic biomarker for many tumors. However, great heterogeneity was shown in predicting overall survival (OS) and progression-free survival (PFS). Emerging studies indicate that the expression levels of members of the miR-200 family are tissue-specific among various tumor tissues, which may be the main reason of the heterogeneity in predicting survival prognosis of tumor patients with the miR-200 family as biomarkers. By further analysis of heterogeneity of the miR-200 family as a biomarker for predicting survival prognosis of patients with different tumors, we expected to provide an accurate basis for the clinical application of the miR-200 family to predict the prognosis of patients with different tumors.

Methods: Eligible published studies were identified by searching the databases of PubMed, Embase and Web of Science. The clinical data of patients in the studies were pooled, and pooled hazard ratios (HR) with 95% confidence intervals (95% CI) were used to calculate the strength of this association. The expressions of miRNAs were extracted from The Cancer Genome Atlas (TCGA). We presented the expressions of each member in miR-200 family in 15 types of cancer by boxplot, and analyzed the correlation among the members of miR-200 family by Spearman method. Different subgroup analyses were then performed based on the correlation among the members of miR-200 family, and the publication bias was assessed using the funnel plot of the Egger bias indicator test.

Results: Of 36 articles, including 15 tumor types and 4644 patients were included to perform meta-analysis. It was found that miR-200 family members can be used as independent protective factors in patients with various tumors but the miR-200 family has a higher heterogeneity in predicting prognosis: OS (HR = 0.82, 95% CI: 0.66-1.03, I² = 85%, P < 0.01) and PFS (HR = 0.81, 95% CI: 0.57-1.16, I² = 97%, P < 0.01). The data from TCGA database were used to analyze the expression levels of the miR-200 family and the results showed that the expression of miR-429 in different cancers is very different, and there are significant differences in expression levels compared with other miR-200 family members; the expression levels of miR-200a and miR-200b in various tumor tissues were similar to each other, respectively; miR-200c and miR-141 showed similar expression levels in each of most types of cancer tissues except ovarian cancer (OC). The expression levels of members of the miR-200 family in breast cancer (BRCA), cervical cancer (CESC), colon cancer (COAD), esophageal cancer (ESCA), head and neck cancer (HNSC), lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are relatively stable, but great variations can be found in the expression levels of miR-200 family members in ovarian cancer (OC), liver cancer (LIHC), renal clear cell carcinoma (KIRC) and renal papillary cell carcinoma (KIRP). Cluster analysis of expression of target genes of miR-200 family in different cancers yielded similar results to the expression level of the miR-200 family. Subgroup analysis of OC, LIHC, GC and LUAD based on expression levels and clustering results reduced or even eliminated the heterogeneity of miR-200 family members in predicting patient outcomes.

Conclusions: Our results convincingly demonstrated that the miR-200 family could serve as a prognostic biomarker for cancers mentioned above and has potential value in clinical practice. MiR-200 family as prognostic biomarkers needs to be performed according to different tumor tissues and correlation between members in miR-200 family.