A Systems Biology Approach Unveils a Critical Role of DPP4 in Upper Gastrointestinal Cancer Patient Outcomes

Abstract

Gastrointestinal (GI) cancers comprise of cancers that affect the digestive system and its accessory organs. The late detection and poor prognosis of GI cancer emphasizes the importance of identifying reliable and precise biomarkers for early diagnosis and prediction of prognosis. The membrane-bound glycoprotein dipeptidyl-peptidase 4 (DPP4), also known as CD26, is ubiquitously expressed and has a wide spectrum of biological roles. The role of DPP4/CD26 in tumor progression in different types of cancers remains elusive. However, the link between DPP4 and tumor-infiltrating cells, as well as its prognostic significance in malignancies, still require further investigation. This study was intended to elucidate the correlation of DPP4 expression and survival along with prognosis, followed by its associated enriched molecular pathways and immune cell marker levels in upper GI cancers. Results demonstrated a strong correlation between increased DPP4 expression and a worse prognosis in esophageal and gastric cancer and the co-expressed common genes with DPP4 were associated with crucial molecular pathways involved in tumorigenesis. Additionally, DPP4 was shown to be significantly linked to several immune infiltrating cell marker genes, including Macrophages (M1, M2 and Tumor Associated Macrophages), neutrophils, Treg, T-cell exhaustion, Th1 and Th2. Overall, our findings suggest that DPP4 may serve as a substantial prognostic biomarker, a possible therapeutic target, as well as it can play a critical role in the regulation of immune cell invasion in patients with gastroesophageal (esophageal, gastroesophageal junction and gastric) cancer. KEY WORDS: DPP4, integrated analysis, GI cancer, gastroesophageal cancer, gastroesophageal junction, prognosis.

FIG. 1:

The differential expression of DPP4 in human cancers. The comparative data obtained from GEPIA represents expression of DPP4 in various tumor and normal tissues. Red color denotes the tumor tissues and green color denotes normal tissue. For the expression data, log2 (TPM+1) was used as the scaling factor. T, tumor; N, normal.

FIG. 2:

The GEPIA boxplot of DPP4 gene expressions in normal and COAD, ESCA, PAAD, STAD cancer tissues. The red box denotes cancer tissue and gray box denotes normal tissues (*P value cutoff 0.01).

FIG. 3:

Comparison of overall survival with upregulated and downregulated expression of DPP4 in different ESCA, STAD and PAAD using Kaplan–Meier plotter. (A and B) DPP4 overexpression is associated with poor OS prognosis in ESCA and STAD, and (C) DPP4 expression exhibited no association with PAAD prognosis. OS, overall survival; HR, hazard ratio.

FIG. 4:

DPP4-associated co-expressed genes in ESCA and STAD. (A and B) The DPP4 associated genes were evaluated by Spearman’s test in ESCA and STAD. Green dots denote positive and red dots denote negative correlations with DPP4, respectively. (C) Intersection of DPP4 associated genes in ESCA and STAD to determine commonly expressed genes.

FIG. 5:

Pathway enrichment analysis of genes co-expressed with DPP4 in the Metascape platform. (A) The 20 most enriched biological pathways associated with DPP4 co-expressed genes are represented. (B) The co-expressed genes with DPP4 were depicted by different colors, which reflected different enrichment pathways. (C) Network of the top 20 biological processes enriched colored by cluster ID.