Review
MicroRNAs in ovarian cancer biology and therapy resistance

https://doi.org/10.1016/j.biocel.2010.01.014Get rights and content

Abstract

Epithelial ovarian cancer is the most common cause of death from gynecological malignancies in the Western world. The overall 5-year survival is only 30% due to late diagnosis and development of resistance to chemotherapy. There is, therefore, a strong need for prognostic and predictive markers to help optimize and personalize treatment hence ameliorating the prognosis of ovarian cancer patients.

Since 2006, an increasing number of studies have indicated an essential role for microRNAs in ovarian cancer tumorigenesis. In this review, we provide an overview of the microRNAs that have been associated with different aspects of ovarian cancer, such as tumor subtype, stage, histological grade, germline mutations in BRCA genes, prognosis and therapy resistance. We highlight the role of the let-7 and miR-200 families, two major microRNA families that are frequently dysregulated in ovarian cancer and have been associated with poor prognosis. Interestingly, both have been implicated in the regulation of the epithelial-to-mesenchymal transition, a cellular transition associated with tumor aggressiveness, tumor invasion and chemoresistance. Furthermore, we discuss several other microRNAs that have been associated with chemotherapy resistance, such as miR-214, miR-130a, miR-27a and miR-451. In the final section, we speculate on the possibilities of microRNA-based therapies and the use of microRNAs as diagnostic tools.

Section snippets

Ovarian cancer

Epithelial ovarian cancer is the most important cause of death from gynecological cancers in the Western world (Parkin et al., 2005). Stage of the disease, histological and molecular cell-biological characteristics have been shown to associate with prognosis or therapy outcome. For example, 20% of ovarian cancers are limited to the ovaries at time of diagnosis (stage 1) and up to 90% of these patients can be cured using currently available therapies (Berek, 2005, Bast et al., 2009). However,

miRNAs and ovarian cancer

The first study suggested that miRNAs also fulfill an important role in ovarian cancer was published in 2006 and showed that approximately 40% of the miRNA genes exhibit altered DNA copy numbers (Zhang et al., 2006). Later on, high expression levels of Dicer, Drosha and eIF6, proteins involved in miRNA maturation (Fig. 1), were shown to be associated with a favorable prognosis of ovarian cancer patients (Flavin et al., 2008, Merritt et al., 2008).

Several studies have reported miRNAs that are

miRNAs and response to chemotherapy

Ovarian cancer is most frequently treated with platinum- and taxane-based chemotherapy. Although initial treatment is successful for 80–90% of the patients, most responders eventually become resistant to a wide range of chemotherapeutic agents. Prediction of those patients that respond to a distinct therapy would help to optimize tailored treatment. Therefore, people have searched for miRNAs that associate with chemosensitivity. These miRNAs might be used as biomarkers but could act as

Towards a miRNA-based therapy

Although it is still a relatively new field, the miRNA studies summarized in this review indicate that miRNAs could play an important role in ovarian cancer diagnosis and treatment.

Since early detection tools are lacking, ovarian cancer is often diagnosed in a late stage which is one of the reasons why ovarian cancer has a high mortality rate. The studies discussed here demonstrate that miRNA expression profiles are different in ovarian cancer compared to normal control tissue, and it might

Acknowledgements

This work was supported by a grant from the Dutch Cancer Society, EMCR 2007-3794.

We thank Hans Kneevel and Jean Helmijr for their help in preparing the figures.

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