Open Access Highly Accessed Research article

Global miRNA expression analysis of serous and clear cell ovarian carcinomas identifies differentially expressed miRNAs including miR-200c-3p as a prognostic marker

Bente Vilming Elgaaen1*, Ole Kristoffer Olstad2, Kari Bente Foss Haug2, Berit Brusletto2, Leiv Sandvik34, Anne Cathrine Staff35, Kaare M Gautvik23 and Ben Davidson36

Author Affiliations

1 Department of Gynecological Oncology, Oslo University Hospital (OUH), The Norwegian Radium Hospital, Postbox 4953 Nydalen 0424, Oslo, Norway

2 Department of Medical Biochemistry, OUH, Ullevaal, Oslo, Norway

3 Faculty of Medicine, University of Oslo, Oslo, Norway

4 Department of Biostatistics and Epidemiology, OUH, Ullevaal, Oslo, Norway

5 Department of Gynecology and Obstetrics, OUH, Ullevaal, Oslo, Norway

6 Department of Pathology, OUH, The Norwegian Radium Hospital, Oslo, Norway

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BMC Cancer 2014, 14:80  doi:10.1186/1471-2407-14-80

Published: 11 February 2014

Abstract

Background

Improved insight into the molecular characteristics of the different ovarian cancer subgroups is needed for developing a more individualized and optimized treatment regimen. The aim of this study was to a) identify differentially expressed miRNAs in high-grade serous ovarian carcinoma (HGSC), clear cell ovarian carcinoma (CCC) and ovarian surface epithelium (OSE), b) evaluate selected miRNAs for association with clinical parameters including survival and c) map miRNA-mRNA interactions.

Methods

Differences in miRNA expression between HGSC, CCC and OSE were analyzed by global miRNA expression profiling (Affymetrix GeneChip miRNA 2.0 Arrays, n = 12, 9 and 9, respectively), validated by RT-qPCR (n = 35, 19 and 9, respectively), and evaluated for associations with clinical parameters. For HGSC, differentially expressed miRNAs were linked to differentially expressed mRNAs identified previously.

Results

Differentially expressed miRNAs (n = 78) between HGSC, CCC and OSE were identified (FDR < 0.01%), of which 18 were validated (p < 0.01) using RT-qPCR in an extended cohort. Compared with OSE, miR-205-5p was the most overexpressed miRNA in HGSC. miR-200 family members and miR-182-5p were the most overexpressed in HGSC and CCC compared with OSE, whereas miR-383 was the most underexpressed. miR-205-5p and miR-200 members target epithelial-mesenchymal transition (EMT) regulators, apparently being important in tumor progression. miR-509-3-5p, miR-509-5p, miR-509-3p and miR-510 were among the strongest differentiators between HGSC and CCC, all being significantly overexpressed in CCC compared with HGSC. High miR-200c-3p expression was associated with poor progression-free (p = 0.031) and overall (p = 0.026) survival in HGSC patients. Interacting miRNA and mRNA targets, including those of a TP53-related pathway presented previously, were identified in HGSC.

Conclusions

Several miRNAs differentially expressed between HGSC, CCC and OSE have been identified, suggesting a carcinogenetic role for these miRNAs. miR-200 family members, targeting EMT drivers, were mostly overexpressed in both subgroups, among which miR-200c-3p was associated with survival in HGSC patients. A set of miRNAs differentiates CCC from HGSC, of which miR-509-3-5p and miR-509-5p are the strongest classifiers. Several interactions between miRNAs and mRNAs in HGSC were mapped.

Keywords:
Ovarian carcinoma; MicroRNA; Microarray; Quantitative PCR; Survival