Background Ovarian 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. Methods Bioinformatics 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. Results CDKN1A 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. Conclusion Collectively, CAF-derived exosomes carrying overexpressed miR-98-5p promote cisplatin resistance in OC by downregulating CDKN1A.

中文翻译：

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癌症相关成纤维细胞衍生的外泌体 microRNA-98-5p 通过靶向 CDKN1A 促进卵巢癌的顺铂耐药。

背景 卵巢癌（OC）是一种死亡率很高的妇科恶性肿瘤。以顺铂为基础的治疗是 OC 患者的典型治疗方案；但是，它可能会导致不利的阻力。目前的研究旨在探索癌症相关成纤维细胞（CAF）衍生的外泌体 microRNA-98-5p（miR-98-5p）在 OC 顺铂耐药中的作用，以及 CDKN1A 的参与。方法采用生物信息学分析方法获得OC中与顺铂耐药相关的差异基因以及可能的上游调控miR。在 OC 细胞中进行功能增益和功能丧失测定后，采用 RT-qPCR 和蛋白质印迹分析来测量 CDKN1A 和 miR-98-5p 表达。应用双荧光素酶报告基因测定来验证 miR-98-5p 和 CDKN1A 之间的靶向关系。用 miR-98-5p 抑制剂处理 CAF，然后分离外泌体并与 OC 细胞共培养。进行CCK-8、集落形成和流式细胞术测定以分别评估细胞增殖、细胞集落形成、细胞周期分布和细胞凋亡。最后，在裸鼠中进行异种移植瘤，以测试外泌体 miR-98-5p 是否会影响 OC 在体内的顺铂耐药性。结果CDKN1A在顺铂敏感OC细胞系中高表达，沉默CDKN1A显着促进顺铂敏感OC细胞的增殖和细胞周期进入，但减少细胞凋亡。miR-98-5p 靶向 CDKN1A 以抑制 CDKN1A 表达。CAF 衍生的外泌体 miR-98-5p 增加了 OC 细胞增殖和细胞周期进入，但抑制了细胞凋亡。此外，外泌体 miR-98-5p 在裸鼠中促进顺铂耐药并下调 CDKN1A。结论总的来说，携带过表达 miR-98-5p 的 CAF 衍生的外泌体通过下调 CDKN1A 促进 OC 中的顺铂耐药。