Fructose-Bisphosphate Aldolase A Regulates Hypoxic Adaptation in Hepatocellular Carcinoma and Involved with Tumor Malignancy

Dig Dis Sci. 2019 Nov;64(11):3215-3227. doi: 10.1007/s10620-019-05642-2. Epub 2019 Apr 30.

Abstract

Background: Hypoxia is an important factor in malignant tumors, and glycolysis is a major metabolic contributor in their development. Glycolytic enzymes have gained increasing attention as potential therapeutic targets because they are associated with cancer-specific metabolism. Fructose-bisphosphate aldolase A (ALDOA), a key glycolytic enzyme, reportedly is associated with hepatocellular carcinoma (HCC). However, its role in pathogenesis and its clinical significance in HCC remain largely unknown.

Aim: To explore the increased expression of ALDOA in HCC in correlation with tumor malignancy, and to investigate the potential regulatory role ALDOA plays in HCC progression through its regulation in hypoxia adaptation.

Methods and results: To better understand ALDOA and its correlation with clinicopathological features of HCC, we analyzed 100 HCC clinical specimens using immunohistochemistry analysis. The results show that the ALDOA expression level is significantly higher in advanced HCC and in HCC with venous invasion. Using in vitro knockdown assays, we showed that higher ALDOA expression was positively associated with cell proliferation, cell cycle, apoptosis, and invasion under both normoxic and hypoxic conditions. Evidence shows that the underlying mechanism is due to the regulatory function of ALDOA in glycolysis, the cell cycle, matrix metalloproteinase-mediated extracellular matrix degradation, and epithelial-mesenchymal transformation.

Conclusions: Data indicated that ALDOA is significantly upregulated in HCC tissue and is closely related to HCC malignancy. ALDOA is likely to regulate HCC progression by regulating HCC tumor cell proliferation, apoptosis, and invasion in both normoxic and hypoxic condition.

Keywords: Epithelial–mesenchymal transition; Fructose-bisphosphate aldolase A; Hepatocellular carcinoma; Hypoxia; Matrix metalloproteinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / biosynthesis
  • Biomarkers, Tumor / genetics
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Proliferation / physiology
  • Fructose-Bisphosphate Aldolase / biosynthesis*
  • Fructose-Bisphosphate Aldolase / genetics
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Neoplasm Invasiveness / pathology
  • Tumor Hypoxia / physiology*

Substances

  • Biomarkers, Tumor
  • ALDOA protein, human
  • Fructose-Bisphosphate Aldolase