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

ABSTRACT Recurrence of hepatocellular carcinoma (HCC) is closely related to the infection of hepatitis B virus (HBV). The HBV x protein (HBx) plays a key role in promoting the malignant transformation of hepatocytes and cancer heterogeneity, but the role of HBx in metabolism influencing the generation of cancer stem cells (CSCs) is still unclear. This study explores HBx‐induced glucose metabolic reprogramming of HCC cells to promote the generation of CSCs. Immunohistochemical analysis of the expression of glucose metabolic reprogramming‐related enzymes and stemness markers in HCC tissues and corresponding paracancer tissues of 30 patients; Western blotting, laser confocal microscopy, and metabolism‐detection kits were applied to analyse the expression of glucose metabolism‐related enzymes and cancer stemness markers and glucose metabolic products; the generation of CSCs was observed by stem cell pellet and soft agar colony formation experiments. Results indicated that the expression of PKM2, HK2, LDHA, CSC‐related proteins, and CD133 and CD44 in HCC tissues was significantly higher than that in the corresponding paracancerous tissues. HBx stimulated the expression of the key enzyme of the Warburg effect and CSC‐related proteins, and these proteins were significantly reduced after interference with the expression of the PKM2 protein. PKM2 and OCT4 interact in HCC cells, and PKM2 has a regulatory effect on OCT4 function. This study found that HBx stimulated the Warburg effect and induced HCC stemness reprogramming by activating the PI3K/AKT signalling pathway; PKM2 played a key role in promoting the initiation of HCC stem cells. Targeting HBx and PKM2 is a new strategy for the treatment of HCC.