Abstract 3068: Integrative tcga analyses identify key microRNAs involved in chemoresistance

Abstract

Abstract Objective. High-grade serous ovarian cancer (HGSOC) is the most common and lethal type of ovarian carcinoma. Our study aims to identify key microRNAs (miRs) that are responsible for promoting chemoresistance in HGSOC. Methods. We developed fast and robust computational algorithm to identify miRs that are significantly associated with improved or worsened survival in HGSOC patients. We subsequently used this algorithm to mine The Cancer Genome Atlas (TCGA) ovarian cancer database to identify miRs that are up-regulated in tumors from patients whose cancer had progressed within 6 months of diagnosis (chemoresistant group) compared to tumors from patients who had no disease progression for more than 2 years (chemosensitive group). We also constructed miRNA-mRNA functional networks for the key miRs identified. The biological roles of selected miRs were subsequently examined in multiple chemoresistant (SKOV3-TR, HeyA8-MDR, and A2780-CP20) ovarian cancer cell lines. Results. From our integrative analyses, we identified several miRs being highly up-regulated or down-regulated in chemoresistant HGSOC (p<0.05, top 10%). To examine the functional roles of these miRs, we transfected miR mimics and anti-miR constructs into taxane or platinum resistant cell lines. We showed that anti-miR-1271 significantly enhanced the sensitivity of taxane-resistant cancer cells (SKOV3-TR and HeyA8-MDR) to paclitaxel and docetaxel treatments. In contrast, transfecting anti-miR-1271 did not alter the sensitivity of A2780-CP20 cells to cisplatin treatment. Conclusion. These data provide the first integrated and functional approach for overcoming chemoresistance using miRs. Citation Format: Fangrong Shen, Sehgal Vasudha, Sherry Wu, Ehsanipour, Ehsan A, Olson Robert C, Ivan, Cristina, Baggerly, Keith A, Ram, Prahlad, Sood, Anil K. Integrative tcga analyses identify key microRNAs involved in chemoresistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3068. doi:10.1158/1538-7445.AM2015-3068