Prognostic role of glycolysis for cancer outcome: evidence from 86 studies

Abstract

Objective: The abnormal expression of the key enzymes in glycolytic pathways, including glucose transporter-1, glucose transporter-3, hexokinase-II, lactate dehydrogenase 5, pyruvate kinase M2, glucose-6-phosphate dehydrogenase, transketolase-like protein 1 and pyruvate dehydrogenase kinase-1 was reported to be associated with poor prognosis of various cancers. However, the association remains controversial. The objective of this study was to investigate the prognostic significance of glycolysis-related proteins.

Materials and methods: We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, using Pubmed and Ovid as search engines and Google Scholar from inception to April 2017. Eighty-six studies with 12,002 patients were included in the study.

Results: Our pooled results identified that glycolysis-related proteins in cancers were associated with shorter overall survival of colorectal cancer (HR 2.33, 95% CI 1.38-3.93, P = 0.002), gastric cancer (HR 1.55, 95% CI 1.31-1.82, P < 0.001), cancer of gallbladder or bile duct (HR 2.16, 95% CI 1.70-2.75, P < 0.001), oral cancer (HR 2.07, 95% CI 1.32-3.25, P < 0.001), esophageal cancer (HR 1.66, 95% CI 1.25-2.21, P = 0.01), hepatocellular carcinoma (HR 2.04, 95% CI 1.64-2.54, P < 0.001), pancreatic cancer (HR 1.72, 95% CI 1.39-2.13, P < 0.001), breast cancer(HR 1.67, 95% CI 1.34-2.08, P < 0.001), and nasopharyngeal carcinoma (HR 3.59, 95% CI 1.75-7.36, P < 0.001). No association was found for lung cancer, ovarian cancer or melanoma. The key glycolytic transcriptional regulators (HIF-1α, p53) were analyzed in parallel to the glycolysis-related proteins, and the pooled results identified that high-level expression of HIF-1α was significantly associated with shorter overall survival (HR 0.57, 95% CI 0.42-0.79, P < 0.001) Furthermore, glycolysis-related proteins linked with poor differentiated tumors (OR 1.81, 95% CI 1.46-2.25, P < 0.001), positive lymph node metastasis (OR 2.73, 95% CI 2.16-3.46, P < 0.001), positive vascular invasion (OR 2.05, 95% CI 1.37-3.07, P < 0.001), large tumor size (OR 2.06, 95% CI 1.80-2.37, P < 0.001), advanced tumor stage (OR 1.58, 95% CI 1.19-2.09, P < 0.001), and deeper invasion (OR 2.37, 95% CI 1.93-2.91, P < 0.001).

Conclusion: Glycolytic transcriptional regulators and glycolysis-related proteins in cancers were significantly associated with poor prognosis, suggesting glycolytic status may be potentially valuable prognostic biomarkers for various cancers.

Keywords: Cancer; Glycolysis; Meta-analysis; Prognostic markers; Survival; Systematic review.

Fig. 1

Flow diagram of study selection

Fig. 2

Forest plot of hazard ratio (HR) for the association between glycolysis-related proteins and OS a, DFS (b) and PFS (c)

Fig. 2

Forest plot of hazard ratio (HR) for the association between glycolysis-related proteins and OS a, DFS (b) and PFS (c)

Fig. 3

Forest plot of hazard ratio (HR) for the association between glycolysis-related proteins and clinicopathological features: large tumor size (a), poor differentiated tumors (b), advanced tumor stage (c), deeper invasion (d), positive lymph node metastasis (e), positive vascular invasion (f), male gender (g), elder patients (h)

Fig. 3

Forest plot of hazard ratio (HR) for the association between glycolysis-related proteins and clinicopathological features: large tumor size (a), poor differentiated tumors (b), advanced tumor stage (c), deeper invasion (d), positive lymph node metastasis (e), positive vascular invasion (f), male gender (g), elder patients (h)

Fig. 4

Sensitivity analysis was performed in present studies for glycolysis-related proteins. a OS; b DFS; c PFS; d tumor grade; e tumor stage; f depth of invasion; g lymph node metastasis; h age; i gender; j vascular invasion; k tumor size

Fig. 4

Sensitivity analysis was performed in present studies for glycolysis-related proteins. a OS; b DFS; c PFS; d tumor grade; e tumor stage; f depth of invasion; g lymph node metastasis; h age; i gender; j vascular invasion; k tumor size

Fig. 5

Begg’s funnel plot for the assessment of publication bias in the present study for glycolysis-related proteins. a OS; b DFS; c PFS; d tumor grade; e tumor stage; f lymph node metastasis; g age; h depth of invasion; i gender; j vascular invasion; k tumor size

Fig. 5

Begg’s funnel plot for the assessment of publication bias in the present study for glycolysis-related proteins. a OS; b DFS; c PFS; d tumor grade; e tumor stage; f lymph node metastasis; g age; h depth of invasion; i gender; j vascular invasion; k tumor size