Email updates

Keep up to date with the latest news and content from BMC Cancer and BioMed Central.

Open Access Highly Accessed Research article

MiR-200c and HuR in ovarian cancer

Silvia Prislei1, Enrica Martinelli1, Marisa Mariani12, Giuseppina Raspaglio1, Steven Sieber2, Gabriella Ferrandina3, Shohreh Shahabi2, Giovanni Scambia13 and Cristiano Ferlini23*

Author Affiliations

1 Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, 00168, Italy

2 Reproductive Tumor Biology Research, Biomedical Laboratory, Department of Obstetrics and Gynecology, Danbury Hospital Research Institute, 131 West Street, Danbury, CT, 06810, USA

3 Department of Oncology, Jean Paul IInd Research Foundation, Campobasso, 86100, Italy

For all author emails, please log on.

BMC Cancer 2013, 13:72  doi:10.1186/1471-2407-13-72

Published: 8 February 2013

Abstract

Background

MicroRNAs in solid malignancies can behave as predictors of either good or poor outcome. This is the case with members of the miR-200 family, which are the primary regulators of the epithelial to mesenchymal transition and have been reported to act as both oncogenes and tumor suppressors. This study assessed the role of miR-200c as regulator of class III β-tubulin (TUBB3), a factor associated with drug-resistance and poor prognosis in ovarian cancer.

Methods

Expression of miR-200c was assessed in a panel of ovarian cancer cell lines with inherent or acquired drug-resistance. Stable overexpression of miR-200c was obtained in A2780 and Hey cell lines. Crosslinking-coupled affinity purification method and ribonucleic-immunoprecipitation assay were used to characterise the complexes between miR-200c, HuR and 3UTR region of TUBB3 mRNA. Nanofluidic technology and immunohistochemistry were used to analyze the expression of HuR, TUBB3 and miR-200c in 220 ovarian cancer patients.

Results

In a panel of ovarian adenocarcinoma cell lines, we observed a direct correlation between miR-200c expression and chemoresistance. In A2780 cells miR-200c targeted TUBB3 3UTR, while a positive correlation was observed between miR-200c and TUBB3 expression in most of the other cell lines. Through the analysis of 3UTR-associated complexes, we found that the miR-200c can increase the association of the RNA binding protein HuR with TUBB3 mRNA, whereas HuR binding enhanced TUBB3 mRNA translation. Most importantly, in our analysis on 220 ovarian cancer patients we observed that overexpression of miR-200c correlated with poor or good outcome depending on the cellular localization of HuR.

Conclusion

This study suggests a model for the combined regulatory activity of miR-200c and HuR on TUBB3 expression in ovarian cancer. When HuR is nuclear, high expression of miR-200c inhibits TUBB3 expression and results in a good prognosis, whereas when HuR occurs in cytoplasm, the same miRNA enhances TUBB3 expression and produces a poor outcome. These findings reveal the usefulness of multidimensional analysis in the investigation of the prognostic role of miRNA expression.

Keywords:
Ovarian cancer; miR-200c; Class III beta-tubulin; HuR; Predictive biomarkers