Published online May 7, 2019. doi: 10.3748/wjg.v25.i17.2086
Peer-review started: January 10, 2019
First decision: February 26, 2019
Revised: March 20, 2019
Accepted: April 10, 2019
Article in press: April 10, 2019
Published online: May 7, 2019
Pancreatic cancer is a highly invasive malignant tumor. Expression levels of the autophagy-related protein microtubule-associated protein 1A/1B-light chain 3 (LC3) and perineural invasion (PNI) are closely related to its occurrence and development. Our previous results showed that the high expression of LC3 was positively correlated with PNI in the patients with pancreatic cancer. In this study, we further searched for differential genes involved in autophagy of pancreatic cancer by gene expression profiling and analyzed their biological functions in pancreatic cancer, which provides a theoretical basis for elucidating the pathophysiological mechanism of autophagy in pancreatic cancer and PNI.
To identify differentially expressed genes involved in pancreatic cancer autophagy and explore the pathogenesis at the molecular level.
Two sets of gene expression profiles of pancreatic cancer/normal tissue (GSE16515 and GSE15471) were collected from the Gene Expression Omnibus. Significance analysis of microarrays algorithm was used to screen differentially expressed genes related to pancreatic cancer. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to analyze the functional enrichment of the differentially expressed genes. Protein interaction data containing only differentially expressed genes was downloaded from String database and screened. Module mining was carried out by Cytoscape software and ClusterOne plug-in. The interaction relationship between the modules was analyzed and the pivot nodes between the functional modules were determined according to the information of the functional modules and the data of reliable protein interaction network.
Based on the above two data sets of pancreatic tissue total gene expression, 6098 and 12928 differentially expressed genes were obtained by analysis of genes with higher phenotypic correlation. After extracting the intersection of the two differential gene sets, 4870 genes were determined. GO analysis showed that 14 significant functional items including negative regulation of protein ubiquitination were closely related to autophagy. A total of 986 differentially expressed genes were enriched in these functional items. After eliminating the autophagy related genes of human cancer cells which had been defined, 347 differentially expressed genes were obtained. KEGG pathway analysis showed that the pathways hsa04144 and hsa04020 were related to autophagy. In addition, 65 clustering modules were screened after the protein interaction network was constructed based on String database, and module 32 contains the LC3 gene, which interacts with multiple autophagy-related genes. Moreover, ubiquitin C acts as a pivot node in functional modules to connect multiple modules related to pancreatic cancer and autophagy.
Three hundred and forty-seven genes associated with autophagy in human pancreatic cancer were concentrated, and a key gene ubiquitin C which is closely related to the occurrence of PNI was determined, suggesting that LC3 may influence the PNI and prognosis of pancreatic cancer through ubiquitin C.
Core tip: In this study, we identified differentially expressed genes based on the autophagy-related protein microtubule-associated protein 1A/1B-light chain 3 (LC3) to analyze the gene expression profile of autophagy in pancreatic cancer. Three hundred and forty-seven genes that have no confirmed association with the autophagy process of human pancreatic cancer cells in previous studies were concentrated, and the key pathways involved in autophagy were enriched. Furthermore, a key gene ubiquitin C which is closely related to the occurrence of perineural invasion (PNI) was determined, suggesting that LC3 may influence the PNI and prognosis of pancreatic cancer through ubiquitin C.