Identification of an autophagy-related gene signature for predicting prognosis and immune activity in pancreatic adenocarcinoma

Abstract

Adenocarcinoma of the pancreas (PAAD) is a cancerous growth that deteriorates rapidly and has a poor prognosis. Researchers are investigating autophagy in PAAD to identify a new biomarker and treatment target. An autophagy-related gene (ARG) model for overall survival (OS) was constructed using multivariate Cox regression analyses. A cohort of the Cancer Genome Atlas (TCGA)-PAAD was used as the training group as a basis for model construction. This prediction model was validated with several external datasets. To evaluate model performance, the analysis with receiver operating characteristic curves (ROC) was performed. The Human Protein Atlas (HPA) and Cancer Cell Line Encyclopedia (CCLE) were investigated to validate the effects of ARGs expression on cancer cells. Comparing the levels of immune infiltration between high-risk and low-risk groups was finished through the use of CIBERSORT. The differentially expressed genes (DEGs) between the low-/high-risk groups were analyzed further via Gene Ontology biological process (GO-BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, which were used to identify potential small-molecule compounds in Connectivity Map (CMap), followed by half-maximal inhibitory concentration (IC50) examination with PANC-1 cells. The risk score was finally calculated as follows: BAK1 × 0.34 + ITGA3 × 0.38 + BAG3 × 0.35 + APOL1 × 0.26–RAB24 × 0.67519. ITGA3 and RAB24 both emerged as independent prognostic factors in multivariate Cox regression. Each PAAD cohort had a significantly shorter OS in the high-risk group than in the low-risk group. The high-risk group exhibited infiltration of several immune cell types, including naive B cells (p = 0.003), plasma cells (p = 0.044), and CD8 T cells (nearly significant, p = 0.080). Higher infiltration levels of NK cells (p = 0.025), resting macrophages (p = 0.020), and mast cells (p = 0.007) were found in the high-risk group than the low-risk group. The in vitro and in vivo expression of signature ARGs was consistent in the CCLE and HPA databases. The top 3 enriched Gene Ontology biological processes (GO-BPs) were signal release, regulation of transsynaptic signaling, and modulation of chemical synaptic transmission, and the top 3 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were MAPK, cAMP, and cell adhesion molecules. Four potential small-molecule compounds (piperacetazine, vinburnine, withaferin A and hecogenin) that target ARGs were also identified. Taking the results together, our research shows that the ARG signature may serve as a useful prognostic indicator and reveal potential therapeutic targets in patients with PAAD.