Identification of Key Genes Involved in Diabetic Peripheral Neuropathy Progression and Associated with Pancreatic Cancer

INTRODUCTION: Diabetes mellitus (DM) patients suffer from high morbidity and premature mortality due to various diabetic complications and even cancers. Therefore, this study aimed to identify key genes involved in the pathogenesis of diabetic peripheral neuropathy (DPN) and pancreatic cancer (PC). METHODS: We analyzed three gene expression profiles (GSE95849, GSE28735 and GSE59953) to obtain differentially expressed genes (DEGs). Then, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was then used to establish a protein–protein interaction (PPI) network. The MCODE and cytoHubba plug-ins of Cytoscape were used to select hub genes. Finally, survival analysis of the hub genes was performed using the Kaplan–Meier plotter and GEPIA online tool. RESULTS: We first analyzed GSE95849 to obtain DPN-related genes. DEGs were obtained from three groups in GSE95849. The DEGs were enriched in the Toll-like receptor signaling pathway, hematopoietic cell lineage and chemokine signaling pathway. Importantly, we identified three shared genes as hub genes, including TLR4, CCR2 and MMP9. We then analyzed and integrated GSE95849 and GSE28735 to obtain genes common in DM and PC. A total of 58 mutual DEGs were identified, and these DEGs were enriched in the ECM-receptor interaction, focal adhesion and pathways in cancer. Five hub genes (including PLAU, MET, CLU, APOL1 and MMP9) were associated with the overall survival of PC patients. However, the results from the analysis of GSE59953 showed that hyperglycemia or TGF-β1 treatment did not affect the expression level of these hub genes, but the DEGs based on hyperglycemia or TGF-β1 treatment were mostly enriched in the ECM-receptor interaction, focal adhesion and pathways in cancer. Finally, functional enrichment analysis of MMP9 showed that significant genes correlated with MMP9 were associated with the tumorigenicity of cancers, insulin resistance, development of DM and inflammation. CONCLUSION: In summary, inflammation and immunity-related pathways may play an important role in DM and DPN, while the ECM-receptor interaction, focal adhesion and pathways in cancer pathways may play significant roles in DM and PC. MMP9 may be used as a prognostic marker for PC and may be helpful for the treatment of DM, DPN and PC.