Phosphoglycerate mutase 1 that is essential for glycolysis may act as a novel metabolic target for predicating poor prognosis for patients with gastric cancer

Abstract

Background: To identify a novel marker for gastric cancer, we examined the usefulness of phosphoglycerate mutase 1 (PGAM1) as a potential diagnostic marker using isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics and evaluated its clinical significance.

Methods: Proteins from a discovery group of four paired gastric cancer tissues and adjacent gastric tissues were labeled with iTRAQ reagents and then identified and quantified using LC-MS/MS. The expression of PGAM1 was further validated in 139 gastric cancer patients using immunohistochemistry. Furthermore, the correlation of PGAM1 expression with clinical parameters was analyzed. Gene set enrichment analysis (GSEA) was performed to identify gene sets that were activated in PGAM1-overexpressing patients with gastric cancer.

Results: PGAM1 was significantly overexpressed in most cancers but particularly so in gastric cancer, with a sensitivity of 82.01% (95% confidence interval [CI]: 75.5%-88.5%) and specificity of 79.13% (95% CI: 72.3%-86%). Its expression was significantly associated with histological grade II and III tumors (p = 0.033), lymph node metastasis (p = 0.031), and TNM III-IV staging (p = 0.025). The area under the receiver operating characteristic (ROC) curve for the detection of PGAM1 overexpression in gastric cancer was 0.718 (p < 0.01). Furthermore, GSEA revealed that several important pathways such as glycolysis pathway and immune pathways were significantly enriched in patients with gastric cancer with PGAM1 overexpression.

Conclusions: This study provided a sensitive method for detecting PGAM1, which may serve as a novel indicator for poor prognosis of gastric cancer, as well as a potent drug target for gastric cancer.

Keywords: Gastric cancer; biomarker; gene set enrichment analysis; iTRAQ; phosphoglycerate mutase 1.

FIGURE 1

Representative MS/MS spectrums of phosphoglycerate mutase 1

FIGURE 2

Expression of phosphoglycerate mutase 1 in the gene expression profiling interactive analysis database. STAD, stomach adenocarcinoma

FIGURE 3

Validation of phosphoglycerate mutase 1 (PGAM1) expression in gastric cancer using immunohistochemistry analysis. PGAM1 was predominantly expressed in plasma (A, gastric benign lesions; B, adjacent cancer tissues; C and D, gastric cancer tissues).

FIGURE 4

ROC curve of PGAM1 in detecting gastric cancer. (AUC = 0.718, p < 0.01)

FIGURE 5

Gene sets activated in the PGAM1‐high expression group, which comprised patients with gastric cancer, according to GSEA analysis. The results showed the TOP 6 pathways enriched in PGAM1‐high‐expression gastric cancer patients (A–F).