Identification of miRNA Signatures Associated with Epithelial Ovarian Cancer Chemoresistance with Further Biological and Functional Validation of Identified Key miRNAs.

摘要

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 and miR-203) that are significantly upregulated in both platinum-resistant cell lines. Additionally, we have also correlated their expression 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. Through this analysis we found that miR-183 correlated with patient survival. The median survival for patients with high expression of miR-183 was 27.2 months versus 53.8 months for those who have low miR-183 expression. In summary, in the 5 months period which we had this grant we were able to validate the dysregulation of several miRNAs in platinum resistant cell lines as well as uncover a novel miRNA that correlates with ovarian cancer patient survival.