Ovarian cancer (OC) is a common reason for gynecologic cancer death. Standard treatments of OC consist of surgery and chemotherapy. However, chemoresistance should be considered. Exosomal miR-21-5p has been shown to regulate the chemosensitivity of cancer cells through regulating pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1). However, the role of miR-21-5p/PDHA1 in OC is unclear. The levels of miR-21-5p and PDHA1 in clinical samples and cells were investigated. Exosomes derived from SKOV3/cisplatin (SKOV3/DDP) cells (DDP-Exos) were isolated and used to treat SKOV3 cells to test DDP-Exos effects on SKOV3 cells. Extracellular acidification rate and oxygen consumption rate were tested with a Seahorse analyzer. Cell apoptosis was analyzed by a flow cytometer. PDHA1 was overexpressed and miR-21-5p was silenced in SKOV3 cells to study the underlying mechanism of miR-21-5p in OC. Quantitative real-time PCR and immunoblots were applied to measure gene expression at mRNA and protein levels. The levels of PDHA1 in DDP-resistant SKOV3 or tumor tissues were significantly decreased while the levels of miR-21-5p were remarkably upregulated. miR-21-5p in DDP-Exos was sharply increased compared to that of Exos. Data also indicated that DDP-Exos treatment suppressed the sensitivity of SKOV3 cells to DDP and promoted cell viability and glycolysis of SKOV3 cells through inhibiting PDHA1 by exosomal miR-21-5p. miR-21-5p derived from DDP-resistant SKOV3 OC cells promotes glycolysis and inhibits chemosensitivity of its progenitor SKOV3 cells by targeting PDHA1. Our data highlights the important role of miR-21-5p/PDHA1 axis in OC and sheds light on new therapeutic development.

中文翻译：

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来自顺铂耐药 SKOV3 卵巢癌细胞的外泌体 miR-21-5p 通过靶向 PDHA1 促进糖酵解并抑制其祖细胞 SKOV3 细胞的化学敏感性

卵巢癌（OC）是妇科癌症死亡的常见原因。OC的标准治疗包括手术和化疗。但是，应考虑化学抗性。外泌体 miR-21-5p 已被证明通过调节丙酮酸脱氢酶 E1 亚基 α1 (PDHA1) 来调节癌细胞的化学敏感性。然而，miR-21-5p/PDHA1 在 OC 中的作用尚不清楚。研究了临床样品和细胞中 miR-21-5p 和 PDHA1 的水平。分离来自 SKOV3/顺铂 (SKOV3/DDP) 细胞 (DDP-Exos) 的外泌体并用于处理 SKOV3 细胞以测试 DDP-Exos 对 SKOV3 细胞的影响。用Seahorse分析仪测试细胞外酸化率和耗氧率。通过流式细胞仪分析细胞凋亡。PDHA1在SKOV3细胞中过表达，miR-21-5p沉默，以研究miR-21-5p在OC中的潜在机制。应用定量实时 PCR 和免疫印迹来测量 mRNA 和蛋白质水平的基因表达。DDP抗性SKOV3或肿瘤组织中PDHA1水平显着降低，而miR-21-5p水平显着上调。与 Exos 相比，DDP-Exos 中的 miR-21-5p 急剧增加。数据还表明，DDP-Exos 处理通过外泌体 miR-21-5p 抑制 PDHA1 抑制 SKOV3 细胞对 DDP 的敏感性并促进 SKOV3 细胞的细胞活力和糖酵解。源自 DDP 抗性 SKOV3 OC 细胞的 miR-21-5p 通过靶向 PDHA1 促进糖酵解并抑制其祖细胞 SKOV3 细胞的化学敏感性。