Differential microRNA expression signatures and cell type-specific association with Taxol resistance in ovarian cancer cells

Abstract

Yong-Wan Kim,1 Eun Young Kim,1 Doin Jeon,1 Juinn-Lin Liu,2 Helena Suhyun Kim,3 Jin Woo Choi,4 Woong Shick Ahn5 1Cancer Research Institute of Medical Science, The Catholic University of Korea, Seoul, Republic of Korea; 2Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, TX, USA; 3Cancer Rehab Laboratory, RH Healthcare Systems Inc, TX, USA; 4Harvard Medical School and Wellman Center for Photomedicine, Cambridge, MA, USA; 5Department of Obstetrics and Gynecology, The Catholic University of Korea, Seoul, Republic of Korea Abstract: Paclitaxel (Taxol) resistance remains a major obstacle for the successful treatment of ovarian cancer. MicroRNAs (miRNAs) have oncogenic and tumor suppressor activity and are associated with poor prognosis phenotypes. miRNA screenings for this drug resistance are needed to estimate the prognosis of the disease and find better drug targets. miRNAs that were differentially expressed in Taxol-resistant ovarian cancer cells, compared with Taxol-sensitive cells, were screened by Illumina Human MicroRNA Expression BeadChips. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to identify target genes of selected miRNAs. Kaplan–Meier survival analysis was applied to identify dysregulated miRNAs in ovarian cancer patients using data from The Cancer Genome Atlas. A total of 82 miRNAs were identified in ovarian carcinoma cells compared to normal ovarian cells. miR-141, miR-106a, miR-200c, miR-96, and miR-378 were overexpressed, and miR-411, miR-432, miR-494, miR-409-3p, and miR-655 were underexpressed in ovarian cancer cells. Seventeen miRNAs were overexpressed in Taxol-resistant cells, including miR-663, miR-622, and HS_188. Underexpressed miRNAs in Taxol-sensitive cells included miR-497, miR-187, miR-195, and miR-107. We further showed miR-663 and miR-622 as significant prognosis markers of the chemo-resistant patient group. In particular, the downregulation of the two miRNAs was associated with better survival, perhaps increasing the sensitivity of cancer cells to Taxol. In the chemo-sensitive patient group, only miR-647 could be a prognosis marker. These miRNAs inhibit several interacting genes of p53 networks, especially in TUOS-3 and TUOS-4, and showed cell line-specific inhibition effects. Taken together, the data indicate that the three miRNAs are closely associated with Taxol resistance and potentially better prognosis factors. Our results suggest that these miRNAs were successfully and reliably identified and would be used in the development of miRNA therapies in treating ovarian cancer. Keywords: microRNA, ovarian cancer, Taxol resistance, Kaplan–Meier survival analysis