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Circ-0005105 activates COL11A1 by targeting miR-20a-3p to promote pancreatic ductal adenocarcinoma progression.

ABSTRACT: Growing evidence indicates that circular RNAs (circRNAs) are closely involved in tumorigenesis, but the association between circRNAs and pancreatic ductal adenocarcinoma (PDAC) is far from clear. Here, we focused on the functional investigation of circ-0005105, a newly identified circRNA, in PDAC progression. In the present study, we assessed circ-0005105 expression in PDAC tissues and cell lines with quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The biological functions of circ-0005105 in cellular proliferation and invasion were identified through gain- and loss-of-function experiments in vitro and in vivo. The interaction between circ-0005105 and the microRNA (miR)-20a-3p-COL11A1 (collagen type XI alpha 1) axis was examined using luciferase reporter and RNA immunoprecipitation assays. We found that circ-0005105 expression was upregulated in both PDAC tissues and cell lines. Higher circ-0005105 expression correlated positively with the malignant clinical phenotype and poor prognosis of patients with PDAC. Gain- and loss-of-function analysis showed that circ-0005105 facilitated both in vitro and in vivo cellular proliferation and invasion. Mechanistically, circ-000510 served as a competing endogenous RNA (ceRNA) of miR-20a-3p and indirectly modulated COL11A1 expression, leading to activation of epithelial-mesenchymal transition (EMT). Rescue experiments suggested that the oncogenic activity of circ-0005105 was dependent on the modulation of the miR-20a-3p-COL11A1 axis. More importantly, COL11A1 overexpression was significantly associated with poor prognosis in PDAC, and silencing COL11A1 reduced PDAC cell tumorigenicity and metastasis. Taken together, our findings confirm for the first time that circ-0005105 has critical functions by regulating the miR-20a-3p-COL11A1 axis. In the clinic, circ-0005105 can act as a potential prognostic marker and therapeutic target in PDAC.

SUBMITTER: Ma G

PROVIDER: S-EPMC8239051 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Circ-0005105 activates COL11A1 by targeting miR-20a-3p to promote pancreatic ductal adenocarcinoma progression.

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