Multi-level integrative analysis of the roles of lncRNAs and differential mRNAs in the progression of chronic pancreatitis to pancreatic ductal adenocarcinoma

Abstract

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors and approximately 5% of patients with chronic pancreatitis (CP) inevitably develop PDAC. This study aims explore the key gene regulation involved in the progression of CP to PDAC, with a particular emphasis on the function of lncRNAs. Results A total of 103 pancreatic tissue samples collected from 11 to 92 patients with CP and PDAC, respectively, were included in this study. After normalizing and logarithmically converting the original data, differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEGs) in each dataset were selected. To determine the main functional pathways of differential mRNAs, we further annotated DEGs using gene ontology (GO) and analyzed the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. In addition, the interaction between lncRNA-miRNA-mRNA was clarified and the protein–protein interaction (PPI) network was constructed to screen for key modules and determine hub genes. Finally, quantitative real-time polymerase chain reaction (qPCR) was used to detect the changes in non-coding RNAs and key mRNAs in the pancreatic tissues of patients with CP and PDAC. In this study, 230 lncRNAs and 17,668 mRNAs were included. There were nine upregulated lncRNAs and 188 downregulated lncRNAs. Furthermore, 2334 upregulated differential mRNAs and 10,341 downregulated differential mRNAs were included in the enrichment analysis. From the KEGG enrichment analysis, cytokine–cytokine receptor interaction, calcium signaling pathway, cAMP signaling pathway, and nicotine addiction exhibited significant differences. Additionally, a total of 52 lncRNAs, 104 miRNAs, and 312 mRNAs were included in the construction of a potential lncRNA-miRNA-mRNA regulatory network. PPI network was established and two of the five central DEGs were created in this module, suggesting that lysophosphatidic acid receptor 1 (LPAR1) and regulator of calcineurin 2 (RCAN2) may play significant roles in the progression from CP to PDAC. Finally, the PCR results suggested that LINC01547/hsa-miR-4694-3p/LPAR1 and LINC00482/hsa-miR-6756-3p/RCAN2 play important roles in the carcinogenesis process of CP. Conclusion Two signaling axes critical in the progression of CP to PDAC were screened out. Our findings will be useful for novel insights into the molecular mechanism and potential diagnostic or therapeutic biomarkers for CP and PDAC.

Keywords

• Chronic pancreatitis
• Pancreatic ductal adenocarcinoma
• lncRNA
• WGCNA
• ceRNAs