MicroRNAs in ovarian cancer biology and therapy resistance

Dept. of Medical Oncology, Josephine Nefkens Institute, Erasmus MC, 3015 GE Rotterdam, The Netherlands.
The international journal of biochemistry & cell biology (Impact Factor: 4.05). 08/2010; 42(8):1282-90. DOI: 10.1016/j.biocel.2010.01.014
Source: PubMed


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.

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Available from: Erik A C Wiemer, Nov 10, 2015
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    • "It has been observed in human ovarian cancers that increased E-cadherin parallels increased levels of miR-200 family members [39]. While the function of the miR-200 family in ovarian cancer is complex, this upregulation is currently under rigorous scrutiny for potential diagnostic and prognostic value. "
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    ABSTRACT: Background The laying hen model of spontaneous epithelial ovarian cancer (EOC) is unique in that it is the only model that enables observations of early events in disease progression and is therefore also uniquely suited for chemoprevention trials. Previous studies on the effect of dietary flaxseed in laying hens have revealed the potential for both amelioration and prevention of ovarian cancer. The objective of this study was to assess the effect of flaxseed on genes and pathways that are dysregulated in tumors. We have used a bioinformatics approach to identify these genes, followed by qPCR validation, immunohistochemical localization, and in situ hybridization to visualize expression in normal ovaries and tumors from animals fed a control diet or a diet containing 10% flaxseed. Results Bioinformatic analysis of ovarian tumors in hens led to the identification of a group of highly up-regulated genes that are involved in the embryonic process of branching morphogenesis. Expression of these genes coincides with expression of E-cadherin in the tumor epithelium. Levels of expression of these genes in tumors from flax-fed animals are reduced 40-60%. E-cadherin and miR200 are both up-regulated in tumors from control-fed hens, whereas their expression is decreased 60-75% in tumors from flax-fed hens. This does not appear to be due to an increase in ZEB1 as mRNA levels are increased five-fold in tumors, with no significant difference between control-fed and flax-fed hens. Conclusions We suggest that nutritional intervention with flaxseed targets the pathways regulating branching morphogenesis and thereby alters the progression of ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-709) contains supplementary material, which is available to authorized users.
    Full-text · Article · Aug 2014 · BMC Genomics
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    • "In 2002, the first evidence of involvement of miRNAs in human cancer came from molecular studies characterizing a deletion in human chronic lymphocytic leukemia, which highlight the importance of two miRNAs, miR-15a and miR-16-1 (Calin et al., 2002). Since their discovery, many studies have underlined the involvement of noncoding RNAs with several conjectures regarding their possible involvement in the evolution of drug resistance (Helleman et al., 2010; van Jaarsveld et al., 2010; Sorrentino et al., 2008). However, the underlying mechanism and its contributions to genome-wide transcriptional changes are still largely unknown (Esquela- Kerscher and Slack, 2006; Calin and Croce, 2006; Bartel, 2004; Ambros, 2004). "
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    ABSTRACT: Ovarian Cancer (OC) is the most lethal gynecological malignancy among women. Over 70% of women with OC are diagnosed in advanced stages and most of these cases are incurable. Although most patients respond well to primary chemotherapy, tumors become resistant to treatment. Mechanisms of chemoresistance in cancer cells may be associated with mutational events and/or alterations of gene expression through epigenetic events. Although focusing on known genes has already yielded new information, previously unknown non-coding RNAs, such as microRNAs (miRNAs), also lead insight into the biology of chemoresistance. In this review we summarize the current evidence examining the role of miRNAs as biomarkers of response and survival to therapy in OC. Beside their clinical implications, we also discuss important differences between studies that may have limited their use as clinical biomarkers and suggest new approaches.
    Full-text · Article · Apr 2014 · Molecular and Cellular Endocrinology
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    • "Many miRNAs have altered expression levels in ovarian cancer compared to normal tissues. In addition, changes in miRNA levels are dependent on and related to the ovarian cancer tissue type, stage, histological type, prognosis, and drug resistance (Table 2) [8, 10, 23–30]. These findings suggest the possibility of early diagnosis of ovarian cancer using miRNAs. "
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    ABSTRACT: Ovarian cancer has a poor prognosis because early detection is difficult and recurrent ovarian cancer is usually drug-resistant. The morbidity and mortality of ovarian cancer are high worldwide and new methods of diagnosis and therapy are needed. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression that are involved in carcinogenesis, metastasis, and invasion. Thus, miRNAs are likely to be useful as diagnostic and prognostic biomarkers and for cancer therapy. Many miRNAs have altered expression in ovarian cancer compared to normal ovarian tissues and these changes may be useful for diagnosis and treatment. For example, deficiencies of enzymes including Dicer and Drosha that are required for miRNA biogenesis may be adverse prognostic factors; miRNAs such as miR-214 and miR-31, which are involved in drug resistance, and the miR-200 family, which is implicated in metastasis, may serve as biomarkers; and transfection of downregulated miRNAs and inhibition of upregulated miRNAs may be effective for treatment of ovarian cancer. Chemotherapy targeting epigenetic mechanisms associated with miRNAs may also be effective to reverse gene silencing.
    Full-text · Article · Apr 2014
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