HBx Drives Liver Cancer Stem Cell Generation Through Stimulating Glucose Metabolic Reprogramming

Area of Science:

• Oncology
• Virology
• Metabolic Engineering

Background:

• Hepatocellular carcinoma (HCC) recurrence is strongly associated with hepatitis B virus (HBV) infection.
• The HBV x protein (HBx) is implicated in hepatocyte malignant transformation and cancer heterogeneity.
• The specific role of HBx in metabolic reprogramming that drives cancer stem cell (CSC) generation in HCC remains unclear.

Purpose of the Study:

• To investigate how HBx-induced glucose metabolic reprogramming promotes CSC generation in HCC.
• To explore the interaction between HBx, glucose metabolism, and stemness in HCC.
• To identify potential therapeutic targets for HCC treatment.

Main Methods:

• Immunohistochemical analysis of glucose metabolic enzymes and stemness markers in HCC tissues.
• Western blotting, laser confocal microscopy, and metabolism-detection kits to analyze protein expression and metabolic products.
• Stem cell pellet and soft agar colony formation assays to assess CSC generation.

Main Results:

• Significantly elevated expression of PKM2, HK2, LDHA, CSC markers (CD133, CD44), and HBx in HCC tissues compared to adjacent tissues.
• HBx upregulates key Warburg effect enzymes and CSC markers, with PKM2 interference reducing these effects.
• PKM2 interacts with OCT4, regulating its function and promoting HCC stemness via the PI3K/AKT pathway.

Conclusions:

• HBx promotes HCC stemness and recurrence by reprogramming glucose metabolism through the PI3K/AKT pathway and PKM2 activation.
• PKM2 is crucial for initiating HCC stem cells.
• Targeting HBx and PKM2 presents a novel therapeutic strategy for HCC.