Emerging evidence has shown that circular RNAs (circRNAs) and DNA methylation play important roles in the causation and progression of cancers. However, the roles of circRNAs and abnormal methylation genes in the tumorigenesis of pancreatic ductal adenocarcinoma (PDAC) are still largely unknown. Expression profiles of circRNA, gene methylation, and mRNA were downloaded from the GEO database, and differentially expressed genes were obtained via GEO2R, and a ceRNA network was constructed based on circRNA-miRNA pairs and miRNA-mRNA pairs. Inflammation-associated genes were collected from the GeneCards database. Then, functional enrichment analysis and protein-protein interaction (PPI) networks of inflammation-associated methylated expressed genes were investigated using Metascape and STRING databases, respectively, and visualized in Cytoscape. Hub genes of PPI networks were identified using the NetworkAnalyzer plugin. Also, we analyzed the methylation, protein expression levels, and prognostic value of hub genes in PDAC patients through the UALCAN, Human Protein Atlas (HPA), and Kaplan-Meier plotter databases, respectively. The circRNA_102049/miR-455-3p/CD80 axis was identified by the ceRNA network and hub genes. In vitro and in vivo experiments were performed to evaluate the functions of circRNA_102049. The regulatory mechanisms of circRNA_102049 and miR-455-3p were explored by RT-PCR, western blot, and dual-luciferase assays. In the present study, twelve hub genes (STAT1, CCND1, KRAS, CD80, ICAM1, ESR1, RAF1, RPS6KA2, KDM6B, TNRC6A, FOSB, and DNM1) were determined from the PPI networks. Additionally, the circRNA_102049 was upregulated in PDAC cell lines. Functionally, the knockdown of circRNA_102049 by siRNAs inhibited cell growth, inflammatory factors, and migratory and invasive potential and promoted cell apoptosis. Mechanistically, circRNA_102049 functioned as a sponge of miR-455-3p and partially reversed the effect of miR-455-3p and consequently upregulated CD80 expression. Our findings showed that circRNA_102049 and methylated hub genes play an important role in the proliferation, apoptosis, migration, invasion, and inflammatory response of PDAC, which might be selected as a promising prognostic marker and therapeutic target for PDAC.

中文翻译：

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circRNA circ_102049 通过靶向 miR-455-3p 激活 CD80 参与胰腺导管腺癌的进展

新出现的证据表明，环状 RNA (circRNAs) 和 DNA 甲基化在癌症的病因和进展中起着重要作用。然而，circRNAs和异常甲基化基因在胰腺导管腺癌（PDAC）的肿瘤发生中的作用仍然未知。从GEO数据库下载circRNA、基因甲基化和mRNA的表达谱，通过GEO2R获取差异表达基因，基于circRNA-miRNA对和miRNA-mRNA对构建ceRNA网络。从 GeneCards 数据库收集炎症相关基因。然后，分别使用 Metascape 和 STRING 数据库研究炎症相关甲基化表达基因的功能富集分析和蛋白质 - 蛋白质相互作用（PPI）网络，并在 Cytoscape 中进行可视化。使用 NetworkAnalyzer 插件识别 PPI 网络的集线器基因。此外，我们分别通过 UALCAN、人类蛋白质图谱 (HPA) 和 Kaplan-Meier 绘图仪数据库分析了 PDAC 患者中枢纽基因的甲基化、蛋白质表达水平和预后价值。circRNA_102049/miR-455-3p/CD80 轴由 ceRNA 网络和中枢基因识别。进行了体外和体内实验以评估circRNA_102049的功能。circRNA_102049 和 miR-455-3p 的调控机制通过 RT-PCR、蛋白质印迹和双荧光素酶测定进行了探索。在本研究中，从 PPI 网络中确定了 12 个中枢基因（STAT1、CCND1、KRAS、CD80、ICAM1、ESR1、RAF1、RPS6KA2、KDM6B、TNRC6A、FOSB 和 DNM1）。此外，circRNA_102049 在 PDAC 细胞系中上调。在功能上，siRNA对circRNA_102049的敲低抑制了细胞生长、炎症因子、迁移和侵袭潜能，并促进了细胞凋亡。从机制上讲，circRNA_102049 充当 miR-455-3p 的海绵并部分逆转 miR-455-3p 的作用，从而上调 CD80 表达。我们的研究结果表明，circRNA_102049 和甲基化枢纽基因在 PDAC 的增殖、凋亡、迁移、侵袭和炎症反应中起重要作用，可能被选为 PDAC 有前景的预后标志物和治疗靶点。circRNA_102049 充当 miR-455-3p 的海绵，部分逆转 miR-455-3p 的作用，从而上调 CD80 表达。我们的研究结果表明，circRNA_102049 和甲基化枢纽基因在 PDAC 的增殖、凋亡、迁移、侵袭和炎症反应中起重要作用，可能被选为 PDAC 有前景的预后标志物和治疗靶点。circRNA_102049 充当 miR-455-3p 的海绵，部分逆转 miR-455-3p 的作用，从而上调 CD80 表达。我们的研究结果表明，circRNA_102049 和甲基化枢纽基因在 PDAC 的增殖、凋亡、迁移、侵袭和炎症反应中起重要作用，可能被选为 PDAC 有前景的预后标志物和治疗靶点。