Abstract
Ovarian cancer is the most lethal gynecological malignancy. The high mortality results from late diagnosis and the development of drug resistance. Drug resistance results from changes in the expression of different drug-resistance genes that may be regulated miRNA. The main aim of our study was to detect changes in miRNA expression levels in two cisplatin (CIS) and two paclitaxel (PAC)—resistant variants of the A2780 drug-sensitive ovarian cancer cell line—by miRNA microarray. The next goal was to identify miRNAs responsible for the regulation of drug-resistance genes. We observed changes in the expression of 46 miRNA that may be related to drug resistance. The overexpression of miR-125b-5p, miR-99a-5p, miR-296-3p, and miR-887-3p and downregulation of miR-218-5p, miR-221-3p, and miR-222-3p was observed in both CIS-resistant cell lines. In both PAC-resistant cell lines, we observed the upregulation of miR-221-3p, miR-222-3p, and miR-4485, and decreased expression of miR-551b-3p, miR-551b-5p, and miR-218-5p. Analysis of targets suggest that expression of important drug-resistant genes like protein Tyrosine Phosphatase Receptor Type K (PTPRK), receptor tyrosine kinase—EPHA7, Semaphorin 3A (SEMA3A), or the ATP-binding cassette subfamily B member 1 gene (ABCB1) can be regulated by miRNA.
Highlights
Epithelial ovarian cancer (EOC) is one of the more aggressive gynecological malignancies and is the fifth leading cause of cancer-related deaths in women [1]
The upregulation of this miR enhanced the sensitivity of OC cell lines to PAC [67]. This miR’s downregulation should enhance PAC resistance, which we could observe in our study. Summarizing this part of the analysis, we can conclude that changes in the expression of miR-205-5p, miR-200c-3p, miR-100-5p, miR-10a-5p, and miR-383-5p are supported by other results, and we suggest their role in PAC resistance and/or ovarian cancer progression
We identified miRNAs that may be specific to CIS or PAC resistance, as their expression changes were observed in both CIS- and PAC-resistant cell lines
Summary
Epithelial ovarian cancer (EOC) is one of the more aggressive gynecological malignancies and is the fifth leading cause of cancer-related deaths in women [1]. According to GLOBOCAN, 295,414 new cases of ovarian cancer and 184,799 of ovarian cancer-related mortality were noted in 2018 [2]. High mortality is related to low diagnosis and development of drug resistance during treatment [3]. About 20% of ovarian cancer patients are primarily resistant to chemotherapy, and nearly 80% respond to first-line chemotherapy. Among these primarily sensitive patients, about 80% will develop drug resistance during treatment [3,4]. This makes the OC an excellent model to study drug resistance development
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