Molecular classification based on hypoxia-associated genes and construction of the prognostic model in Chronic Obstructive Pulmonary Disease

Hypoxia exerts a great influence on multiple cancer development while the role of hypoxia in chronic obstructive pulmonary disease (COPD) remains an enigma. Here we focused on differential expression genes (DEGs) between COPD and negative normal groups and the hypoxia-associated genes (HRGs) to explore the association between hypoxia and COPD progression. GSE54837 and GSE151052 datasets in the Gene Expression Omnibus (GEO) database were collected to perform data processing and DEGs in two datasets were analyzed (GSE54837 as the training set and GSE151052 as the validation set). 7 overlapping hypoxia-related DEGs (HRDEGs, TPD52, and RORA down-regulated vs PPP1R15A, DDIT3, DUSP1, and PDK3 up-regulated) were identified in DEGs of GSE54837 and HRGs. Also, the expression of 6 HRDEGs was investigated in GSE151052. PPP1R15A, DUSP1, and PDK3 were also up-regulated in the GSE151052 dataset. Three HRDEGs (TPD52, DDIT3, and DUSP1) were finally picked out to further analysis according to the best method. In addition, we discovered that Amygdalus Communis Vas could target DUSP1, and diclofenac was able to simultaneously target three HRDEGs. Subsequently, COPD samples were divided into three subtypes (C1, C2, and C3) according to three HRDEGs in both the training set and validation set. There was a positive relationship between TPD52 and immune features while DDIT3 and DUSP1 were negatively associated with immune features in GSE54837. The immune cells and immune features between COPD and normal groups differed from each other. C1 subtypes carried more significant immune signatures. We observed that the KEGG pathways between the three subtypes differed from each other. Interestingly, small molecules including TTNPB, arachidonyltrifluoromethane, MK.886, MS.275, and exisulind were more sensitive to COPD with severe hypoxic subtypes. Our findings revealed the association between hypoxia and COPD, which offered a novel layer for developing promising therapeutic targets in COPD treatment.