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

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.