Abstract
Pancreatic ductal adenocarcinoma is a common malignant tumor with a poor prognosis. Autophagy activity changes in both cancer cells and microenvironment and affects the progression of pancreatic ductal adenocarcinoma. The purpose of this study was to predict the prognostic autophagy regulatory genes and their role in the regulation of autophagy in pancreatic ductal adenocarcinoma. We draw conclusions based on gene expression data from different platforms: GSE62165 and GSE85916 from the array platform, TCGA from the bulk RNA-seq platform, and GSE111672 from the single-cell RNA-seq platform. At first, we detected differentially expressed genes in pancreatic ductal adenocarcinoma compared with normal pancreatic tissue based on GSE62165. Then, we screened prognostic genes based on GSE85916 and TCGA. Furthermore, we constructed a risk signature composed of the prognostic differentially expressed genes. Finally, we predicted the probable role of these genes in regulating autophagy and the types of cell expressing these genes. According to our screening criteria, there were only two genes: MET and RIPK2, selected into the development of the risk signature. However, evaluated by log-rank tests, receiver operating characteristic curves, and calibration curves, the risk signature was worth considering its clinical application because of good sensitivity, specificity, and stability. Besides, we predicted that both MET and RIPK2 promote autophagy in pancreatic ductal adenocarcinoma by gene set enrichment analysis. Analysis of single-cell RNA-seq data from GSE111672 revealed that both MET and RIPK2 were expressed in cancer cells while RIPK2 was also expressed in monocytes and neutrophils. After comprehensive analysis, we found that both MET and RIPK2 are related to the prognosis of pancreatic ductal adenocarcinoma and provided some associated clues for clinical application and basic experiment research.
Highlights
Pancreatic cancer has become one of the leading causes of cancer mortality worldwide [1]
25 autophagy regulatory genes were upregulated and the 22 ones were downregulated in Pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissues (Figures 2(a) and 2(b))
The univariate Cox proportional hazards regression analysis showed that 6 autophagy regulatory genes were significantly associated with overall survival (OS) of PDAC patients in the GSE85916 group (p < 0:05) (Figure 2(c))
Summary
Pancreatic cancer has become one of the leading causes of cancer mortality worldwide [1]. Poor prognosis results from loss of surgical opportunities due to the advanced tumor stage at diagnosis and high resistance to chemotherapy and radiation [5, 6]. Clinicopathological characteristics and some biomarkers have been used to predict patients’ prognosis, identification of transcriptional markers and development of novel methodology for accurate prediction of PDAC outcome are still encouraged. Autophagy plays an important role in both the maintenance of homeostasis and the progress of tumors. In a normal organizational environment, autophagy maintains cell homeostasis to prevent diseases by supporting mammalian development, regulating metabolism at different nutritious states, and disposing damaged proteins and organelles [7]. Autophagy suppresses tumor at the initial stage by being involved in removing dysfunctional mitochondria and redox-active aggregates of ubiquitinated proteins, disposal of micronuclei, and degradation of retrotransposing
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