The role of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in hepatocellular carcinoma

Metabolic reprogramming such as glycolysis even in aerobic environments (Warburg effect) is a hallmark of different types of cancer including hepatocellular carcinoma (HCC). The bifunctional enzyme 6-phosphofructo-2-kinase/furctose-2,6-biphosphatase 3 (PFKFB3) is an important regulator of glycolysis. PFKFB3 has been implicated in the progression of several types of cancer. However, its role in HCC is largely unknown.

The aim of this study was to analyze the expression and function of PFKFB3 in HCC.

Methods and results: PFKFB3 mRNA and protein expression is significant higher in different human HCC cell lines (Hep3B, PLC, SNU449 and Huh7) compared to primary human hepatocytes as analyzed by RT-qPCR and Westernblotting. PFKFB3 was further increased in HCC cells under hypoxic conditions, and also in human HCC tissues. PFKFB3 showed a significant correlation with the glucose transporter GLUT1, a known marker for hypoxia. RNAi-mediated PFKFB3 suppression in HCC cells resulted in reduced glucose consumption and lactate production. Furthermore, PFKFB3 suppressed HCC cells showed significantly reduced colony formation and growth, proliferation and migratory activity. Similar results were found in HCC cells treated with a specific PFKFB3 inhibitor. In HCC patients, high PFKFB3 expression correlated with poor progression free and overall survival.

Conclusion: Our data indicate that enhanced PFKFB3 expression induces glycolysis and acts as a protumorigenic factor in HCC. Therefore, PFKFB3 appears as a potential prognostic marker and therapeutic target in HCC.

Publication History

Article published online:
20 January 2025