Abstract
Cumulating evidence indicates that dysregulation of microRNAs (miRNAs) plays a central role in the initiation, progression, and drug resistance of cancer cells. However, the specific miRNAs contributing to drug resistance in ovarian cancer cells have not been fully elucidated. Aimed to identify potential miRNAs involved in platinum resistance, we performed a miRNA expression profile in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells, and we found several differentially abundant miRNAs in the pair of cell lines. Notably, miR-18a-5p (miR-18a), a member of the oncogenic associated miR-17-92 cluster, was decreased in cisplatin-resistant as compared with cisplatin-sensitive cells. Real-time PCR analysis confirmed these findings. We then studied the biological, molecular, and therapeutic consequences of increasing the miR-18a levels with oligonucleotide microRNA mimics (OMM). Compared with a negative control OMM, transient transfection of a miR-18a-OMM reduced cell growth, cell proliferation, and cell invasion. Intraperitoneal injections of miR-18a-OMM-loaded folate-conjugated liposomes significantly reduced the tumor weight and the number of nodules in ovarian cancer-bearing mice when compared with a control-OMM group. Survival analysis using the Kaplan-Meier plotter database showed that ovarian cancer patients with high miR-18a levels live longer in comparison to patients with lower miR-18a levels. Bioinformatic analyses, real-time-PCR, Western blots, and luciferase reporter assays revealed that Matrix Metalloproteinase-3 (MMP-3) is a direct target of miR-18a. Small-interfering RNA (siRNA)-mediated silencing of MMP-3 reduced cell viability, cell growth, and the invasiveness potential of cisplatin-resistant ovarian cancer cells. Our study suggests that targeting miR-18a is a plausible therapeutic strategy for cisplatin-resistant ovarian cancer.
Highlights
Ovarian cancer is the deadliest gynecological malignancy, provoking around 239,000 new cases and 152,000 deaths worldwide annually [1]
Since the greatest effect was observed using the miR-18a-oligonucleotide microRNA mimics (OMM), we focused our studies on the role of this miRNA in the cisplatin resistance of ovarian cancer cells
Transient transfection of miR-18a OMM in A2780CP20 cells reduced the luciferase activity compared to CNT-OMM (P
Summary
Ovarian cancer is the deadliest gynecological malignancy, provoking around 239,000 new cases and 152,000 deaths worldwide annually [1]. The standard treatment for women with ovarian cancer consists of debulking cytoreductive surgery and platinum/taxane combination chemotherapy [2]. Despite the initial effectiveness of the combined chemotherapy, more than 70% of ovarian cancer patients relapse and they become resistant to platinum-based treatment [3]. Other mechanisms of cisplatin resistance include activation of cell survival pathways, dysregulation of oncogenes, tumor suppressor genes, long-non-coding RNAs and microRNAs [7]. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level. Evidence indicates that miRNAs potentially regulate more than 60% of the protein-coding genes [8]. MiRNAs bind mainly to the 3′ untranslated region (3′UTR) of their target messenger RNAs (mRNAs) and induce mRNA degradation or inhibit translation initiation [9]. Downregulated microRNAs are named tumor-suppressor miRNAs [11]
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