Abstract
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.
Highlights
Pancreatic cancer is the seventh leading cause of global cancer-associated death, with an estimated 432,242 deaths in 2018 [1], and is predicted to become in 2030 the second leading cause of cancer-related death [2, 3]
The clinical stage analysis of hub genes was investigated by using the GEPIA2 database, and the results suggest that the expression levels of CD80 and intercellular adhesion molecule 1 (ICAM1) were significantly increased in various tumor stages (Supplementary Figure S2)
We found that high mRNA expression of signal transducer and activator of transcription 1 (STAT1), cyclin D1 (CCND1), KRAS, CD80, and RAF1 and low mRNA expression of KDM6B, trinucleotide repeat-containing adaptor 6A (TNRC6A), Hypomethylation GSE49149
Summary
Pancreatic cancer is the seventh leading cause of global cancer-associated death, with an estimated 432,242 deaths in 2018 [1], and is predicted to become in 2030 the second leading cause of cancer-related death [2, 3]. Pancreatic ductal adenocarcinoma (PDAC) is the most common class of aggressive malignancies in the exocrine pancreas, accounting for approximately 90% of cases, with an unsatisfactory prognosis [4]. This fatal disease is characterized by a few obvious clinical presentation, metastasis, and recurrence that contribute to the poor quality of life of patients [5]. Curative resection, classical chemotherapy, and radiotherapy are the main therapeutic strategies [6]. Despite the great advances of clinical technology, the outcomes remain unsatisfactory and the five-year survival rate of PDAC patients remains below 5% [5]. There is an urgent need to increase the understanding of underlying molecular
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