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. 2021 Feb;9(4):358.
doi: 10.21037/atm-21-295.

Aberrant lactate dehydrogenase A signaling contributes metabolic signatures in pancreatic cancer

Wenna Jiang  1 , Lu Qiao  1 , Duo Zuo  1 , Di Qin  2 , Jiawei Xiao  1 , Haohua An  1 , Yanhui Wang  1 , Xinwei Zhang  1 , Yu Jin  1 , Li Ren  1
Affiliations

Aberrant lactate dehydrogenase A signaling contributes metabolic signatures in pancreatic cancer

Wenna Jiang et al. Ann Transl Med. 2021 Feb.

Abstract

Background: Pancreatic cancer (PC) has the lowest 5-year survival rate; therefore, new early screening methods and therapeutic targets are still urgently required. Emerging technologies such as metabolomic-based liquid biopsy may contribute to the field. We found aberrant lactate dehydrogenase A (LDHA) signaling to be an unfavorable biomarker for PC.

Methods: A total of 9 genes of the glycolysis pathway were detected by enrichment analysis in the PC Gene Expression Omnibus (GEO) dataset. The relationship between LDHA/pyruvate kinase (PKM)/fructose biphosphate aldolase A (ALDOA)/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and patient survival was analyzed by Kaplan-Meier plotting analysis of The Cancer Genome Atlas (TCGA). The detection of changing metabolites in the serum of PC patients was performed using a nuclear magnetic resonance (NMR) spectrometer.

Results: We found LDHA was an independent predictor of overall survival (OS) in PC patients (P<0.001). Consistent with genetic aberrance of LDHA, we identified significant alterations in patients' glycolysis-related metabolites, including upregulation of lactic acid and downregulation of pyruvic acid. A 0.956 area under the curve (AUC) was achieved using the combinative metabolites score of lactic acid, pyruvic acid, citric acid, and glucose to distinguish PC from healthy controls.

Conclusions: Aberrant LDHA signaling is an unfavorable biomarker for PC and consequential metabolic changes constitute potential diagnostic signatures of PCs.

Keywords: Biomarkers; aerobic glycolysis; gene expression; pancreatic cancer (PC); serum metabolites.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-295). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Overall analysis workflow in this article.
Figure 2
Figure 2
Differential expression and glycolysis-related gene expression in PC. (A) Heatmap analysis of DEGs in the pancreatic cancer GEO dataset. (B) Bubble diagram of the top 10 enriched pathways in KEGG (top 10). (C) Heatmap analysis of glycolysis-related gene expression. (D) The expression levels of 9 genes of the glycolysis pathway in the cancer and normal cohorts in the GEO dataset. PC, pancreatic cancer; DEGs, differentially expressed genes; GEO, Gene Expression Omnibus; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 3
Figure 3
Kaplan-Meier plots of 4 genes in the glycolysis pathway.
Figure 4
Figure 4
Metabolite changing characteristics in PC serum. (A) Sankey diagram of serum metabolite variety in cancer (cancer/normal). (B) Comparison of the cancer and normal metabolomes via principal component analysis. (C) Violin plot of serum glycolysis-related metabolites in cancer and normal cohorts. (D) ROC curves of glucose, citric acid, lactic acid, pyruvic acid, and their combination (all). PC, pancreatic cancer; ROC, receiver operating characteristic.
Figure 5
Figure 5
LDHA overexpression and metabolites alternation in pancreatic cancer specimens. (A) Clinical parameters and contrast-enhanced CT scans before and after operation in three cases. (B) IHC staining of LDHA in 3 PC and adjacent normal tissues. Magnification, ×200; scale bars, 50 µm. (C) Glycolysis-related metabolites score alternation in 3 pancreatic cancer patients before and after operation. LDHA, lactate dehydrogenase-A; CT, computed tomography; IHC, immunohistochemistry; PC, pancreatic cancer.
Figure 6
Figure 6
Serum metabolite variety coincides with the overexpression of LDHA. LDHA, lactate dehydrogenase-A.
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