MicroRNAs in ovarian cancer: Current status and future perspectives
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 improving 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 chapter, 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. Although the targets of most microRNAs are still under investigation, for some microRNAs they have been identified in functional studies. The functional processes in which these microRNAs play a role include epithelial-to-mesenchymal transition (EMT), p53 pathway, proliferation and maintenance of the cancer stem cells and will be discussed in light of their observed association with ovarian cancer. For instance, the let-7 and miR-200 families are aberrantly expressed in ovarian cancer and have been associated with poor prognosis. While Let-7 is associated with RAS activity, both families have been implicated in the regulation of EMT, which is an early step in carcinogenesis associated with tumor aggressiveness, tumor invasion and resistance to chemotherapy. In addition, the miR-34 genes, miR-34a and miR-34b/c, are regulated by p53 and add a new, challenging layer of complexity to the p53 network. Since p53 is frequently mutated in ovarian carcinoma and plays a role in development of cancer and platinumbased chemotherapy resistance, the miR34 family could be of merit to ovarian cancer diagnosis and therapy and may also be associated with stem cell self-renewal. Similarly, miR-31, miR-221, miR-222, miR-20a and miR-100 have been linked to the pathogenesis and treatment of ovarian cancer and target genes like p27 and p57 (proliferation), mTOR (part of the PI3kinase pathway) and Kallikrein-related peptidases. In addition, we discuss several other microRNAs that have been associated with chemotherapy resistance, such as miR-214, miR-199a and miR-130a. In the final section, we speculate on the possibilities for the use of microRNAs as diagnostic tools and microRNA-based therapies taking into account the knowledge gained from siRNA-based therapies. Results from initial studies of miRNAs by silencing and re-expression in mammalian cell-culture systems and animal in vivo models are critically reviewed.