Hepatitis B virus (HBV) is one of predisposing factors for hepatocellular carcinoma (HCC). The role of HBV x protein (HBx) in mediating the induction and maintenance of cancer stemness during HBV-related HCC attracts considerable attention, but the exact mechanism has not been clearly elucidated. Here, ABCG2-dependent stem-like side population cells, which are thought to be liver cancer stem cells (LCSCs), were present in HCC cells, and the fraction of this subset was increased in HBx-expressing HCC cells. In addition, glycolysis was upregulated in LCSCs and HBx-expressing HCC cells, and intervention of glycolysis attenuated cancer stem-like phenotypes. Mitochondria play an important role in the maintenance of energy homeostasis, BNIP3L-dependent mitophagy was also activated in LCSCs and HBx-expressing HCC cells, which triggered a metabolic shift toward glycolysis. In summary, we proposed a positive feedback loop, in which HBx induced BNIP3L-dependent mitophagy which upregulated glycolytic metabolism, increasing cancer stemness of HCC cells in vivo and in vitro. BNIP3L might be a potential therapeutic target for intervention of LCSCs-associated HCC. Anti-HBx, a monoclonal antibody targeting intracellular HBx, had the potential to delay the progression of HBV infection related-HCC.
Keywords: BNIP3L; glycolysis metabolism reprogramming; hepatitis B virus x protein; liver cancer stem cells; mitophagy.