The Significance of MicroRNAs Expression in Regulation of Extracellular Matrix and Other Drug Resistant Genes in Drug Resistant Ovarian Cancer Cell Lines.

Dominika Kazmierczak,Marcin Rucinski,Radoslaw Januchowski,Karolina Sterzynska,Michal Nowicki,Karol Jopek,Barbara Ginter-Matuszewska

doi:10.3390/ijms21072619

Dominika Kazmierczak, Marcin Rucinski + Show 5 more

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https://doi.org/10.3390/ijms21072619

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Abstract

Ovarian cancer rates the highest mortality among all gynecological malignancies. The main reason for high mortality is the development of drug resistance. It can be related to increased expression of drug transporters and increased expression of extracellular matrix (ECM) proteins. Our foremost aim was to exhibit alterations in the miRNA expression levels in cisplatin (CIS), paclitaxel (PAC), doxorubicin (DOX), and topotecan (TOP)—resistant variants of the W1 sensitive ovarian cancer cell line—using miRNA microarray. The second goal was to identify miRNAs responsible for the regulation of drug-resistant genes. According to our observation, alterations in the expression of 40 miRNAs were present. We could observe that, in at least one drug-resistant cell line, the expression of 21 miRNAs was upregulated and that of 19 miRNAs was downregulated. We identified target genes for 22 miRNAs. Target analysis showed that miRNA regulates key genes responsible for drug resistance. Among others, we observed regulation of the ATP-binding cassette subfamily B member 1 gene (ABCB1) in the paclitaxel-resistant cell line by miR-363 and regulation of the collagen type III alpha 1 chain gene (COL3A1) in the topotekan-resistant cell line by miR-29a.

Highlights

Ovarian cancer poses a growing threat to women’s lives and health and occupies the first place in mortality among gynecological cancers [1]
Some of the micro RNA (miRNA) encoding genes may be located within exons of other genes. miRNAs are classified in groups called miRNA families, and most of them are transcribed by RNA polymerase II [15]
An miRNA profiling study showed that the pattern of miRNA expression in cancer tissues compared to normal tissues was very different [19]. miRNA can perform suppressor or oncogenic functions in cancers

Summary

Introduction

Ovarian cancer poses a growing threat to women’s lives and health and occupies the first place in mortality among gynecological cancers [1]. The tissue specific mechanisms are associated with tumor vascularization, cell density in the tumor, and expression of extracellular matrix proteins (ECM) [9]. All of these change drug distribution in the tumor tissue, decreasing their availability to tumor cells. MiRNAs are short (19–29 nucleotides), single-stranded, non-coding RNA molecules with a phosphate residue (5 end) and a hydroxyl group (3 end) [12] They play an important regulatory role in the expression of genes in both animals and plants [12].

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