Abstract
BackgroundOvarian cancer (OC) is a gynecological malignancy with a high mortality. Cisplatin-based treatment is the typical treatment regimen for OC patients; however, it may cause unfavorable resistance. The current study intends to explore the function of cancer-associated fibroblast (CAF)-derived exosomal microRNA-98-5p (miR-98-5p) in cisplatin resistance in OC, and the participation of CDKN1A.MethodsBioinformatics analysis was employed in order to obtain cisplatin resistance-related differential genes in OC as well as possible upstream regulatory miRs. After gain- and loss-of-function assays in OC cells, RT-qPCR and western blot analysis were employed to measure CDKN1A and miR-98-5p expression. Dual luciferase reporter assay was applied to verify the targeting relationship between miR-98-5p and CDKN1A. CAFs were treated with miR-98-5p inhibitor, and then exosomes were isolated and co-cultured with OC cells. CCK-8, colony formation and flow cytometry assays were conducted to assess cell proliferation, cell colony formation, cell cycle distribution and cell apoptosis, respectively. At last, xenograft tumor in nude mice was carried out to test whether exosomal miR-98-5p could affect cisplatin resistance in OC in vivo.ResultsCDKN1A was highly expressed in cisplatin-sensitive OC cell lines, and silencing CDKN1A significantly promoted proliferation and cell cycle entry but decreased apoptosis in cisplatin-sensitive OC cells. miR-98-5p targeted CDKN1A to inhibit CDKN1A expression. CAF-derived exosomal miR-98-5p increased OC cell proliferation and cell cycle entry, but suppressed cell apoptosis. Furthermore, exosomal miR-98-5p promoted cisplatin resistance and downregulated CDKN1A in nude mice.ConclusionCollectively, CAF-derived exosomes carrying overexpressed miR-98-5p promote cisplatin resistance in OC by downregulating CDKN1A.
Highlights
Ovarian cancer (OC) is a gynecological malignancy with a high mortality
reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis displayed that the expression patterns of CDKN1A in OC cell lines were as follows: HOSE piCs > SKOV3 > A2780 > SKOV3/cisplatin > A2780/cisplatin (Fig. 1D-F), indicating that higher CDKN1A expression in cisplatin-sensitive OC cell lines as well as lower CDKN1A expression in cisplatin-resistant OC cell lines
The findings demonstrated that cancer-associated fibroblasts (CAFs)-derived exosomes could deliver miR-98-5p to facilitate cisplatin resistance in OC, which was achieved by regulating CDKN1A
Summary
Ovarian cancer (OC) is a gynecological malignancy with a high mortality. Cisplatin-based treatment is the typical treatment regimen for OC patients; it may cause unfavorable resistance. The current study intends to explore the function of cancer-associated fibroblast (CAF)-derived exosomal microRNA-98-5p (miR-98-5p) in cisplatin resistance in OC, and the participation of CDKN1A. Cancer-associated fibroblasts (CAFs), an abundant stromal cell type in various cancers [6], have been reported to cause unsatisfactory prognosis of OC [7]. CAFs are able to secrete exosomes under the tumor microenvironment, and it has been reviewed that exosomes are implicated in both cancer progression and drug resistance [8]. Exosomes are identified as membrane vesicles of 40–100 nm, which are of endocytic origin secreted by the majority of cell types in vitro [9]. MiR-98-5p participated in the control of cisplatin resistance in epithelial OC, the expression of which was correlated with unfavorable outcome of epithelial OC patients [11]. Hsa-miR-98-5p was indicated as a promising target in clinical cisplatin treatment for non-small cell lung cancer [12]
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