Abstract GMM-059: SHEAR STRESS DOWNREGULATION OF MIR-199A-3P DRIVES CHEMORESISTANCE IN OVARIAN CANCER CELLS

Abstract

Abstract Ovarian cancer is leading cause of deaths among all gynecological malignancies. The presence of intrinsic and acquired drug resistance are major challenges in the treatment and clinical management of ovarian cancer. Ovarian cancer cells typically cluster into tumor spheroids and float in the ascitic fluid, which are characteristic of the aggressiveness of these tumor cells. We have recently developed a three-dimensional microfluidic platform with tumor spheroids and continuous fluidic flow to closely emulate the physiological condition in the ascites of ovarian cancer patients. Using this model, we showed for the first time that clinically relevant levels of ascitic shear stress induced drug resistance in ovarian tumor spheroids. Such chemoresistance was mediated through the increased expression of ABC-binding cassette transporter G2 and P-glycoprotein. By profiling the microRNAs (miRNAs) expression patterns under flow conditions, we identified miR-199a-3p as a critical mechanosensitive miRNA that was downregulated under shear stress through regulating the miRNA biogenesis machinery. miR-199a-3p expression was found to be inversely correlated with enhanced drug resistance properties and chemoresistant ovarian cancer sublines. Ectopic expression of miRNA-199a-3p could reverse the shear stress-induced expression of ABC-binding cassette transporter G2 and P-glycoprotein in ovarian tumor spheroids, confirming that the effect was miR-199a-3p specific. Taken together, these findings highlight the importance of shear stress-mediated decrease of miR-199a-3p in the regulation of drug response in ovarian cancer, which provide new insights in the understanding of cancer biology and potential effective treatment. Citation Format: Shan-Shan Li, Carman K. M. Ip, Ho-Cheung Shum, Alice S. T. Wong. SHEAR STRESS DOWNREGULATION OF MIR-199A-3P DRIVES CHEMORESISTANCE IN OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-059.