MicroRNAs in ovarian cancer biology and therapy resistance.
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.
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ABSTRACT: Background Tumor hypoxia is one of the features of tumor microenvironment that contributes to chemoresistance. miRNAs have recently been shown to play important roles in tumorigenesis and drug resistance. Moreover, hypoxia also regulates the expression of a series of miRNAs. However, the interaction between chemoresistance, hypoxia and miRNAs has not been explored yet. The aim of this study is to understand the mechanisms activated/inhibited by miRNAs under hypoxia that induce resistance to chemotherapy-induced apoptosis. Methods TaqMan low-density array was used to identify changes in miRNA expression when cells were exposed to etoposide under hypoxia or normoxia. The effects of miR-196b overexpression on apoptosis and cell proliferation were studied in HepG2 cells. miR-196b target mRNAs were identified by proteomic analysis, luciferase activity assay, RT-qPCR and western blot analysis. Results Results showed that hypoxia down-regulated miR-196b expression that was induced by etoposide. miR-196b overexpression increased the etoposide-induced apoptosis and reversed the protection of cell death observed under hypoxia. By a proteomic approach combined with bioinformatics analyses, we identified IGF2BP1 as a potential target of miR-196b. Indeed, miR-196b overexpression decreased IGF2BP1 RNA expression and protein level. The IGF2BP1 down-regulation by either miR-196b or IGF2BP1 siRNA led to an increase in apoptosis and a decrease in cell viability and proliferation in normal culture conditions. However, IGF2BP1 silencing did not modify the chemoresistance induced by hypoxia, probably because it is not the only target of miR-196b involved in the regulation of apoptosis. Conclusions In conclusion, for the first time, we identified IGF2BP1 as a direct and functional target of miR-196b and showed that miR-196b overexpression reverses the chemoresistance induced by hypoxia. These results emphasize that the chemoresistance induced by hypoxia is a complex mechanism. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0349-6) contains supplementary material, which is available to authorized users.Molecular Cancer 04/2015; 14(1). DOI:10.1186/s12943-015-0349-6 · 5.40 Impact Factor
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ABSTRACT: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and is the fifth leading cause of cancer deaths in women. Developing adjuvant therapy to circumvent drug resistance represents an important aspect of current initiatives to improve survival in women with advanced EOC. A regulatory molecule that can act on multiple genes associated with a chemoresistant phenotype will be the ideal target for the development of therapeutics to overcome resistance and miRNAs constitute promising tools in this regard. In this review, we discuss the emerging role of miRNAs in regulating EOC phenotype with a focus on prognostic and therapeutic importance of miRNAs and the possibility of miRNA modulation as a tool to improve efficacy of chemotherapy in EOC.Biomarkers in Medicine 03/2015; 9(3):241-57. DOI:10.2217/bmm.14.108 · 2.86 Impact Factor