High expression of SPP1 in patients with chronic obstructive pulmonary disease (COPD) is correlated with increased risk of lung cancer

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and fixed airflow obstruction. Patients with COPD have increased risk of lung cancer (LC), and the coexistence of both diseases is associated with poorer survival. However, the mechanisms predisposing patients with COPD to LC development and poor prognosis remain unclear. Gene expression profiles were downloaded from the Gene Expression Omnibus. Twenty-two data sets were included (n = 876). We identified 133 DEGs and 145 DEGs in patients with COPD and LC compared with healthy controls, respectively. There were 1544 DEGs in patients with LC and coexisting COPD compared with COPD, and these DEGs are mainly involved in the cell cycle, DNA replication, p53 signalling and insulin signalling. The biological processes primarily associated with these DEGs are oxidation reduction and apoptosis. SPP1 was the only overlapping DEG that was up-regulated in patients with COPD and/or LC, and this was validated by qPCR in an independent cohort. The area under the curve value for SPP1 was 0.893 (0.822-0.963) for the prediction of LC in patients with COPD. High expression of SPP1 in patients with LC was associated with shorter survival time. Up-regulation of SPP1 may be associated with increased risk of LC in patients with COPD and therefore may have potential as a therapeutic target for LC in patients with COPD.

Keywords: SPP1; bioinformatics; chronic obstructive pulmonary disease; lung cancer; meta-analysis.

Fig. 1

Volcano plots of DEGs. (A) COPD vs HC in epithelial cell of GPL570; (B) LC vs HC in epithelial cell of GPL96; (C) LC vs HC in lung tissue of GPL570; (D) LC vs HC in lung tissue of GPL96; (E) LC coexisting with COPD vs COPD in epithelial cell of GPL1708. Red and green dots denote up‐regulated and down‐regulated genes, respectively.

Fig. 2

Venn diagrams of the DEGs. (A) The DEGs in LC vs HC across all sample types and platforms; (B) the overlapping DEG that was up‐regulated in patients with COPD, LC and LC coexisting with COPD.

Fig. 3

Heatmap of the top 50 DEGs (top 25 up‐regulated and 25 down‐regulated genes) in patients with LC and coexisting COPD vs COPD. Red indicates up‐regulation, and blue indicates down‐regulation.

Fig. 4

The top 10 significant enriched GO terms based on DEGs related to LC coexisting with COPD vs COPD by DAVID. (A) Biological process; (B) cellular component; (C) molecular function.

Fig. 5

ROC analysis revealed that the relative expression levels of SPP1 in the lungs could predict coexisting LC in patients with COPD, and AUC value with 95% CI was 0.893 (95% CI: 0.822–0.963).

Fig. 6

Survival analysis of SPP1 in LC by using the Kaplan–Meier plotter database.

Fig. 7

qPCR validation of SPP1 expression in a cancer cohort. Levels of SPP1 expression in lung tissues between non‐smoker controls (n = 9), smoker controls (n = 15), COPD (n = 13), NSCLC (n = 8) and NSCLC coexisting with COPD (n = 16) were compared by the Mann–Whitney test. Data are presented as median (interquartile range). **P < 0.01. ***P < 0.001.