Circular RNAs (circRNAs) are increasingly implicated in regulating human carcinogenesis. Previous work showed the oncogenic activity of circ_0018289 in cervical cancer. However, the molecular basis underlying the modulation of circ_0018289 in cervical carcinogenesis is still not fully understood. The levels of circ_0018289, microRNA (miR)-183-5p, and transmembrane p24 trafficking protein 5 (TMED5) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Ribonuclease (RNase) R and subcellular localization assays were used to characterize circ_0018289. Cell proliferation was detected by the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (Edu) assays. Cell apoptosis and tube formation were assessed by flow cytometry and tube formation assays, respectively. A dual-luciferase reporter assay was performed to confirm the direct relationship between miR-183-5p and circ_0018289 or TMED5. The role of circ_0018289 in tumor growth was gauged by mouse xenograft experiments. Circ_0018289 was overexpressed in cervical cancer tissues and cells. Circ_0018289 silencing impeded cell proliferation, enhanced cell apoptosis, and suppressed angiogenesis in vitro, as well as diminished tumor growth in vivo. Mechanistically, circ_0018289 targeted and regulated miR-183-5p by binding to miR-183-5p, and circ_0018289 regulated cervical cancer development and angiogenesis partially through miR-183-5p. Moreover, TMED5 was directly targeted and inhibited by miR-183-5p through the perfect complementary sites in TMED5 3′UTR, and TMED5 knockdown phenocopied miR-183-5p overexpression in suppressing cervical cancer development and angiogenesis. Furthermore, circ_0018289 induced TMED5 expression by competitively binding to shared miR-183-5p. Our observations identified the circ_0018289/miR-183-5p/TMED5 regulatory network as a novel molecular basis underlying the modulation of cervical carcinogenesis.

中文翻译：

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一种新型 circ_0018289/miR-183-5p/TMED5 调控网络在宫颈癌发展中的鉴定

环状 RNA (circRNA) 越来越多地参与调节人类致癌作用。以前的工作显示了 circ_0018289 在宫颈癌中的致癌活性。然而，circ_0018289 调控宫颈癌发生的分子基础仍不完全清楚。通过定量实时聚合酶链反应 (qRT-PCR) 或蛋白质印迹法测定 circ_0018289、microRNA (miR)-183-5p 和跨膜 p24 转运蛋白 5 (TMED5) 的水平。核糖核酸酶 (RNase) R 和亚细胞定位测定用于表征 circ_0018289。通过 Cell Counting Kit-8 (CCK-8) 和 5-ethynyl-2'-deoxyuridine (Edu) 测定法检测细胞增殖。分别通过流式细胞术和管形成测定评估细胞凋亡和管形成。进行双荧光素酶报告基因测定以确认 miR-183-5p 与 circ_0018289 或 TMED5 之间的直接关系。circ_0018289 在肿瘤生长中的作用是通过小鼠异种移植实验来衡量的。Circ_0018289 在宫颈癌组织和细胞中过表达。Circ_0018289 沉默在体外阻碍细胞增殖、增强细胞凋亡和抑制血管生成，并减少体内肿瘤生长。机制上，circ_0018289 通过与 miR-183-5p 结合来靶向和调节 miR-183-5p，而 circ_0018289 部分通过 miR-183-5p 调节宫颈癌的发展和血管生成。此外，miR-183-5p通过TMED5 3'UTR中的完美互补位点直接靶向和抑制TMED5，和 TMED5 敲低在抑制宫颈癌发展和血管生成中的 phenocopied miR-183-5p 过表达。此外，circ_0018289 通过竞争性结合共享的 miR-183-5p 诱导 TMED5 表达。我们的观察发现 circ_0018289/miR-183-5p/TMED5 调控网络是调控宫颈癌发生的新分子基础。