Identification of miRNA Signatures Associated with Epithelial Ovarian Cancer Chemoresistance with Further Biological and Functional Validation of Identified Key miRNAs
Technical Report,30 Jan 2014,29 Jan 2015
Case Western Reserve University Cleveland United States
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Epithelial ovarian cancer EOC is the most lethal gynecologic malignancy in the United States. One major obstacle in the clinical management of the disease is the high incidence of recurrence after cytotoxic chemotherapy and the development of platinum resistance. Given the crucial importance to overcome chemotherapy resistance to platinum therapy, we hypothesize that miRNA profiling in EOC cell lines and surgical specimens with varying chemosensitivities will uncover a potential predictive fingerprint for individualized therapy, while further biological validation of these miRNAs signatures will allow for the development of novel therapeutic strategies to enhance chemosensitivity. Through mircoarray analysis of miRNAs differentially expressed in an in vitro model of acquired carboplatin resistance consisting of EOC cell lines sensitive to carboplatin, A2780, and its resistant variants, CP20 moderately resistant and CP70 resistant, we identified a panel of miRNAs that correlate with carboplatin response. We uncovered four miRNAs miR-23b, miR-132, miR-183. miR-181a and miR-203 that are significantly upregulated in both platinum-resistant cell lines. Additionally, we found that miR-181a was also correlated with several clinical parameters in a cohort of ovarian tumor specimens from women diagnosed with stage III, grade 3, papillary serous adenocarcinoma all treated with platinum-based chemotherapy. Furthermore, we uncovered the biological relevance of this miRNA. We found that miR-181a induced platinum-resistance through the maintenance of cancer stem cells thourgh the regulation for TGFb and Wnt signaling pathway.