Abstract
We investigated the role of the competing endogenous RNA (ceRNA) network in the development and progression of pancreatic adenocarcinoma (PAAD). We analyzed the expression profiles of PAAD and normal pancreatic tissues from multiple GEO databases and identified 457 differentially expressed circular RNAs (DEcircRNAs), 19 microRNAs (DEmiRNAs) and 1993 mRNAs (DEmRNAs). We constructed a ceRNA network consisting of 4 DEcircRNAs, 3 DEmiRNAs and 149 DEmRNAs that regulates the NF-kappa B, PI3K-Akt, and Wnt signaling pathways. We then identified and validated five hub genes, CXCR4, HIF1A, ZEB1, SDC1 and TWIST1, which are overexpressed in PAAD tissues. The expression of CXCR4, HIF1A, ZEB1, and SDC1 in PAAD was regulated by circ-UBAP2 and hsa-miR-494. The expression of CXCR4 and ZEB1 correlated with the levels of M2 macrophages, T-regulatory cells (Tregs) and exhausted T cells in the PAAD tissues. The expression of CXCR4 and ZEB1 positively correlated with the expression of CTLA-4 and PD-1. This suggests that CXCR4 and ZEB1 proteins inhibit antigen presentation and promote immune escape mechanisms in PAAD cells. In summary, our data suggest that the circUBAP2-mediated ceRNA network modulates PAAD by regulating the infiltration and function of immune cells.
Highlights
Pancreatic adenocarcinoma (PAAD) is the most commonly occurring pancreatic cancer, and the seventh leading cause of tumor-related death in both men and women worldwide [1]
We found that circCLEC17A is aberrantly overexpressed in PAAD tissues from females compared to males (Supplementary Figures 2A–2D)
After integrating the results of the Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network analyses, we identified 5 hub genes that were closely related to PAAD tumorigenesis, namely, CX-C Motif Chemokine Receptor 4 (CXCR4), HypoxiaInducible Factor 1 Subunit Alpha (HIF1A), Zinc Finger E-Box Binding Homeobox 1 (ZEB1), Syndecan 1 (SDC1) and Twist Family BHLH Transcription Factor 1 (TWIST1)
Summary
Pancreatic adenocarcinoma (PAAD) is the most commonly occurring pancreatic cancer, and the seventh leading cause of tumor-related death in both men and women worldwide [1]. It is often asymptomatic during the early stages. The treatment of PAAD has improved in recent years, thanks to the availability of newer chemotherapeutic drugs and advances in surgical techniques, the survival rates of PAAD patients remain very low. The majority of the patients are diagnosed with advanced stage PAAD, which is not amenable for surgical therapy [2].
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