Novel Insights into PGM2L1 as a Prognostic Biomarker in Cholangiocarcinoma: Implications for Metabolic Reprogramming and Tumor Microenvironment Modulation

Abstract

Cholangiocarcinoma (CCA) is a highly lethal malignancy and the most common adenocarcinoma of the hepatobiliary system. PGM2L1 belongs to the α-D-phosphohexomutase superfamily and functions as a glucose 1,6-bisphosphate (G16BP) synthase. There is growing evidence to provide an association its function to cancer metabolism and progression. However, the molecular mechanisms of PGM2L1 in CCA development remain lacking in evidence. In this study, we found that CCA patients with high PGM2L1 expression had the poorest prognosis. We identified two methylation sites (cg15214137 and cg03699633) within the PGM2L1 gene and their prognostic relevance. We further investigated the relationship between PGM2L1 expression and tumor-infiltrating immune cells, with a particular focus on neutrophils in CCA. Functional enrichment analyses further revealed that high PGM2L1 expression was associated with the Wnt signaling pathway, glycolytic metabolism, and the recruitment of neutrophils. Collectively, these findings suggest that PGM2L1 may serve as an independent prognostic biomarker and is closely linked to tumor immune infiltration and metabolic reprogramming in CCA.

Keywords: PGM2L1; cholangiocarcinoma; glycolytic metabolism; tumor-infiltrating immune cells.

Figure 1

Workflow of the study analysis process. Workflow creation was performed using Biorender (https://app.biorender.com).

Figure 2

PGM2L1 ranked as the top gene in Kaplan-Meier analysis, showing differential mRNA levels between normal and CCA samples and correlating with overall survival in CCA. (A) Top 20 genes based on Kaplan-Meier survival analysis in TCGA-CHOL from UALCAN website (https://ualcan.path.uab.edu) (B) PGM2L1 mRNA expression is higher in normal tissue (n = 9) than that in CCA (n = 36) from the UALCAN website (https://ualcan.path.uab.edu). (C) Overall survival in CCA patients with high (red) and low (blue) PGM2L1 expression was analyzed using Kaplan-Meier survival curves. Mean ± SD, ***: p < 0.001.

Figure 3

The DNA methylation of PGM2L1 in CCA of TCGA (A) Promoter methylation levels of PGM2L1 between Normal tissue and CCA. (B) Heatmap of DNA methylation expression level of PGM2L1 gene in CCA. (C-D) Prognostic value of single CpG of the PGM2L1 gene in CCA. The threshold of significance was Log-Rank Test p value <0.05.

Figure 4

Correlation of PGM2L1 expression with immune infiltration level in CCA. (A) PGM2L1 expression levels in CCA from TCGA-CHOL database was determined by TIMER. (B) Prognostic roles of PGM2L1 and immune-related factor in CCA from TCGA-CHOL database was determined by TIMER. * p < 0.05.

Figure 5

Gene sets and pathway enriched in PGM2L1 phenotype. (A) GO showed significant signaling pathways with PGM2L1 high and low expression groups. (B) KEGG showed significantly different signaling pathways with PGM2L1 high and low expression groups. (C) GSEA analysis revealed differential enrichment of genes with PGM2L1 high and low expression groups. (Nominal p-value < 0.05). GSEA, Gene Set Enrichment Analysis; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.