The common drawback of miRNA expression profiling studies is a lack of agreement among several studies. With reference to previous studies, a logical solution to the problem is to determine the agreement among the miRNA expression profiling studies using different platforms and observe which differentially expressed miRNAs are consistently reported. Notably, cumulative data had demonstrated that several consistently expressed miRNAs, maybe as candidate biomarker, were showed in some profiling studies of colorectal carcinoma  and lung cancer , respectively.
However, the general and accurate study of consistent miRNA expression in ovarian cancer versus normal ovary or benign ovarian tumors profiles had not been reported before. In this study, we observed that a total of 185 differentially expressed miRNAs were reported in the 8 miRNA expression profiling studies, but only 17 miRNAs were reported in at least three or more expression profiling studies. Excitingly, among the 17 miRNAs, 5 promising differentially miRNAs (miR-200a, miR-100, miR-141, miR-200b, and miR-200c) were reported with the consistent direction in four or more studies. It is that MiR-100 was down-regulated and the others all up-regulated in EOC tissues. Then, in order to determine whether the above five identified miRNAs had been previously validated to have diagnostic or prognostic values as biomarkers in EOC, a literature review and validation experiment were performed. Gratifyingly, the data of using EOC and normal ovarian specimens collected in our center was consistent with the findings of profiling studies.
Particularly, all of them (miR-200a, miR-200b, miR-200c, and miR-141), four up-regulated miRNAs of the five most consistently expressed miRNA among the eight profiling studies, belong to the miR-200 family. MiR-200a and miR-200b are located on chromosome 1, while miR-200c and miR-141 are on chromosome 12. The most prominent targets of the miR-200 family are two E-box binding transcription factors, ZEB1 and ZEB2, keys regulators of a complex network of transcriptional repressors regulating E-cadherin expression and epithelial polarity. Consistent with this function, the miR-200 family was recently identified as a marker, as well as a powerful regulator of the epithelial-to-mesenchymal transition (EMT). Indeed, EMT played an important role in carcinogenesis and tumor progression, when tumor cells undergo a change from a differentiated to a dedifferentiated, more aggressive and invasive phenotype. Furthermore, the increased expression of miR-200a might underlie genomic amplification. Frequent chromosomal gains in that region have been reported in ovarian carcinoma . The inhibition of miR-200b increased the sensitivity to gemcitabine in cholangiocarcinoma cell lines , and thereby, increased expression of miR-200b may result in poor response to antineoplastic drugs. Moreover, inhibition of miR-141 using anti-miR-141 decreased cell growth in choloangiocarcinoma cell lines . Accordingly, miR-200b and miR-141 could be a novel target for enhancing chemosensitivity or inducing cell death in ovarian cancer. Additionally, high expression of miR-200a was identified to correlate with decreased progression-free survival and overall survival for EOC patients significantly, even as miR-200c [9, 16]. As a result, miR-200 family might serve as a molecular marker for the prediction of the prognosis and the evaluation of the response to chemotherapy for EOC patients.
MiR-100, another important consistent expressed miRNA in this study, may be as another candidate biomarker in ovarian cancer, which has been reported to be down-regulated in 5 profiling studies but up-regulated only in one study. MiR-100 represses mTOR (mammalian target of rapamycin) signaling and increases sensitivity to the cancer drug everolimus (rapamycin analog RADOO1) in cell lines derived from clear cell carcinomas . mTOR is a serine/threonine kinase and downstream effector of the AKT signaling pathway, which has also been shown to be a possible therapeutic target in both cisplatin-sensitive and cisplatin-resistant clear cell ovarian carcinoma [24, 25]. Additionally, miR-100 inhibited cell proliferation by suppressing mTOR in esophageal squamous cell carcinoma (ESCC) cell lines and Low miR-100 expression was associated with worse overall survival in ESCC patients . Recently, Peng et al. showed that miR-100 can significantly inhibit growth of EOC cells by targeting PLK1 (Polo-like kinase-1) and more importantly, miR-100 may be as an independent predictor for the prognosis evaluation of ovarian cancer patients. Thus, they suggested the miR-100/PLK1 signaling pathway may provide therapeutic targets for human EOCs .
Conclusively, this systematic review and validation experiment demonstrated four up-regulated miRNAs (miR-200a, miR-200b, miR-200c and miR-141) and one down-regulated miRNA (miR-100) are promising important candidate biomarkers for EOC. However, the shortcomings of this study are review of profiling studies with retrospective and limited profiles. Further clinical and mechanistic studies focusing on these miRNA need to be performed for their clinical significance and the underlying roles in tumorigenesis of EOC.