Abstract
BackgroundColorectal cancer (CRC) is a common malignant solid tumor with an extremely low survival rate after relapse. Previous investigations have shown that autophagy possesses a crucial function in tumors. However, there is no consensus on the value of autophagy-associated genes in predicting the prognosis of CRC patients. This work screens autophagy-related markers and signaling pathways that may participate in the development of CRC, and establishes a prognostic model of CRC based on autophagy-associated genes.MethodsGene transcripts from the TCGA database and autophagy-associated gene data from the GeneCards database were used to obtain expression levels of autophagy-associated genes, followed by Wilcox tests to screen for autophagy-related differentially expressed genes. Then, 11 key autophagy-associated genes were identified through univariate and multivariate Cox proportional hazard regression analysis and used to establish prognostic models. Additionally, immunohistochemical and CRC cell line data were used to evaluate the results of our three autophagy-associated genes EPHB2, NOL3, and SNAI1 in TCGA. Based on the multivariate Cox analysis, risk scores were calculated and used to classify samples into high-risk and low-risk groups. Kaplan-Meier survival analysis, risk profiling, and independent prognosis analysis were carried out. Receiver operating characteristic analysis was performed to estimate the specificity and sensitivity of the prognostic model. Finally, GSEA, GO, and KEGG analysis were performed to identify the relevant signaling pathways.ResultsA total of 301 autophagy-related genes were differentially expressed in CRC. The areas under the 1-year, 3-year, and 5-year receiver operating characteristic curves of the autophagy-based prognostic model for CRC were 0.764, 0.751, and 0.729, respectively. GSEA analysis of the model showed significant enrichment in several tumor-relevant pathways and cellular protective biological processes. The expression of EPHB2, IL-13, MAP2, RPN2, and TRAF5 was correlated with microsatellite instability (MSI), while the expression of IL-13, RPN2, and TRAF5 was related to tumor mutation burden (TMB). GO analysis showed that the 11 target autophagy genes were chiefly enriched in mRNA processing, RNA splicing, and regulation of the mRNA metabolic process. KEGG analysis showed enrichment mainly in spliceosomes. We constructed a prognostic risk assessment model based on 11 autophagy-related genes in CRC.ConclusionA prognostic risk assessment model based on 11 autophagy-associated genes was constructed in CRC. The new model suggests directions and ideas for evaluating prognosis and provides guidance to choose better treatment strategies for CRC.
Highlights
Colorectal cancer (CRC) is a prevalent disease worldwide [1]
To further understand whether autophagy-associated differentially expressed genes (DEGs) were associated with the survival of CRC patients, we obtained 30 prognosis-associated genes by univariate Cox analysis (Figure 1B), which were screened and modeled by further multivariate Cox analysis (Table 2)
Increasing numbers of studies confirm the importance of autophagy in CRC at various stages [20, 21]
Summary
Colorectal cancer (CRC) is a prevalent disease worldwide [1]. Even with improvements in living standards and changes in dietary structure, the morbidity and fatality of CRC have remained high in recent years [2]. Autophagy is a lysosome-dependent degradation pathway characterized by cytoplasmic vacuolation [3] It can degrade damaged structures in the cytoplasm and produce small organic molecules, and other substances for protein compound and energy metabolism, enabling cells to adapt to hypoxia and starvation [4]. The process of autophagy is modulated by multifarious complex signaling molecules [5]. Failure of this regulatory mechanism is closely related to tumor development, neurodegenerative diseases, and aging [6,7,8]. This work screens autophagy-related markers and signaling pathways that may participate in the development of CRC, and establishes a prognostic model of CRC based on autophagy-associated genes
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