Ovarian cancer is the malignant tumor of the female reproductive system with the highest fatality rate. Tolerance to chemotherapeutic drugs such as paclitaxel (PTX) occurring in the very early stage is one of the important factors of the poor prognosis of ovarian cancer. Herein, we aim to study the dysregulation of a particular circular RNA (circRNA), circCELSR1 (hsa_circ_0063809), and its role in the progression and PTX resistance of ovarian cancer. The high expression of circCELSR1 in PTX-resistant tissues of ovarian cancer and PTX-resistant ovarian cancer cells (SKOV3/PTX and HeyA-8/PTX) was determined by microarray analyses and quantitative real-time PCR. Cell Counting Kit-8 (CCK-8) assays were performed to investigate the effect of circCELSR1 on PTX sensitivity of ovarian cancer cells. Flow cytometer assays were used to detect cell cycle and apoptosis of ovarian cancer cells. The effect of circCELSR1 on ovarian cancer cells was assessed and . The microRNA (miRNA) sponge mechanism of circRNAs was demonstrated using dual-luciferase reporter and RNA immunoprecipitation assays. By microarray (5 PTX-resistant ovarian cancer tissues νs 5 PTX-sensitive ovarian cancer tissues) and qRT-PCR (36 normal ovarian tissues and ovarian cancer tissues) we identified circCELSR1 to be dramatically highly expressed in ovarian cancer samples and correlated with PTX resistance. Compared with sensitive cell lines, circCELSR1 was also highly expressed in PTX-resistant ovarian cancer cell lines, and circCELSR1 silencing enhanced PTX-induced cytotoxicity in ovarian cancer cells. Meanwhile, the inhibition of circCELSR1 also caused ovarian cancer cell G/G arrest and an increase in apoptosis. studies revealed that circCELSR1 was stably inhibited in a xenograft mouse model and inhibited the growth of ovarian cancer. Furthermore, we demonstrated that circCELSR1 acts as a sponge for miR-1252 and verified that forkhead box 2 (FOXR2) is a novel target of miR-1252. In this study, we explored the specific mechanisms of PTX resistance and tumor progress of ovarian cancer due to circCELSR1; presented the circCELSR1-miR-1252-FOXR2 axis and its role in ovarian cancer drug sensitivity and progression; and suggest that the results may provide an experimental basis for clinical application.

中文翻译：

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circCELSR1 (hsa_circ_0063809) 通过 miR-1252 调节 FOXR2 表达，促进卵巢癌细胞对紫杉醇的耐药性


卵巢癌是女性生殖系统死亡率最高的恶性肿瘤。极早期发生的对紫杉醇（PTX）等化疗药物的耐受是卵巢癌预后不良的重要因素之一。在此，我们的目标是研究特定环状 RNA (circRNA) circCELSR1 (hsa_circ_0063809) 的失调及其在卵巢癌进展和 PTX 耐药中的作用。通过微阵列分析和实时定量PCR确定circCELSR1在卵巢癌PTX耐药组织和PTX耐药卵巢癌细胞（SKOV3/PTX和HeyA-8/PTX）中高表达。进行细胞计数试剂盒-8 (CCK-8) 检测以研究 circCELSR1 对卵巢癌细胞 PTX 敏感性的影响。采用流式细胞仪检测卵巢癌细胞的细胞周期和凋亡。评估了 circCELSR1 对卵巢癌细胞的影响。使用双荧光素酶报告基因和 RNA 免疫沉淀测定证明了 circRNA 的 microRNA (miRNA) 海绵机制。通过微阵列（5 个 PTX 耐药性卵巢癌组织 νs 5 个 PTX 敏感性卵巢癌组织）和 qRT-PCR（36 个正常卵巢组织和卵巢癌组织），我们发现 circCELSR1 在卵巢癌样本中显着高表达，并与 PTX 耐药性相关。与敏感细胞系相比，circCELSR1在PTX耐药的卵巢癌细胞系中也高表达，并且circCELSR1沉默增强了PTX诱导的卵巢癌细胞的细胞毒性。同时，circCELSR1的抑制还引起卵巢癌细胞G/G阻滞和细胞凋亡增加。 研究表明，circCELSR1 在异种移植小鼠模型中受到稳定抑制，并抑制卵巢癌的生长。此外，我们证明了 circCELSR1 作为 miR-1252 的海绵，并验证了 forkhead box 2 (FOXR2) 是 miR-1252 的新靶标。在本研究中，我们探讨了circCELSR1导致的卵巢癌PTX耐药和肿瘤进展的具体机制；介绍了 circCELSR1-miR-1252-FOXR2 轴及其在卵巢癌药物敏感性和进展中的作用；并表明该结果可为临床应用提供实验依据。