Comprehensive Analysis of a circRNA-Mediated Competing Endogenous RNA Network in Pancreatic Adenocarcinoma

Abstract

Background: The circRNA-miRNA-mRNA competing endogenous RNA Network (ceRNA) plays a critical role in tumorigenesis but remains largely unknown in pancreatic adenocarcinoma (PAAD). This study aimed to construct a ceRNA network and explore its relationship with the PAAD immune microenvironment. Methods: Differentially expressed circRNAs, miRNAs and mRNAs were extracted from open access PAAD datasets. The ceRNA network was built using the relation prediction tool for circRNA-miRNA-mRNA. Subsequently, hub genes were identified and validated, survival analyses were performed and the role of hub genes in the tumor microenvironment was explored. Findings: We established a ceRNA network consisting of 4 DEcircRNAs, 3 DEmiRNAs and 149 DEmRNAs. DEcircRNAs, including circ-UBAP2, circ-HIBADH, circ-TADA2A and circ-CLEC17A, were identified to play a central role in the ceRNA network. Moreover, the identified DEmRNAs were enriched in the NF-kappa B signaling pathway, PI3K-Akt signaling pathway and Wnt signaling pathway. After integrating the results of the enrichment analysis and the weight of each gene in the PPI network, we identified 5 hub genes. Notably, 4 out of 5 hub genes, including CXCR4, HIF1A, ZEB1 and SDC1, might be regulated by circ-UBAP2/hsa-mir-494. The results also showed that CXCR4 and ZEB1 could facilitate the immune infiltration of M2 macrophages, Tregs and exhausted T cells. In addition, CXCR4 and ZEB1 were positively correlated with CTLA-4 and PD-1 obviously, indicating that these two hub genes might inhibit antigen presentation and promote immune escape. Interpretation: Altogether, the ceRNA network may play an important role in the immune microenvironment and tumorigenesis of PAAD. Funding: This work was supported by Zhejiang Natural Sciences Foundation Grant (LQ18H160008, LQ17H160011, LY17H160029), the Ten Thousand Plan Youth Talent Support Program of Zhejiang Province, the Zhejiang Medical and Health Science and Technology Project (2016KYB290, 2016ZDB007, 2017ZD021), the Zhejiang Medical Innovative Discipline Construction Project-2016, and the Hangzhou Health and Family planning and Science and Technology Project (OO20190347) Declaration of Interest: The authors declare no competing interests.