Aerobic glycolysis enhances HBx-initiated hepatocellular carcinogenesis via NF-κBp65/HK2 signalling

• Published in: Journal of experimental & clinical cancer research 2022-11, Vol.41 (1), p.329-19, Article 329
• Main Authors: Chen, Lingjun, Lin, Xianyi, Lei, Yiming, Xu, Xuan, Zhou, Qi, Chen, Yan, Liu, Huiling, Jiang, Jie, Yang, Yidong, Zheng, Fengping, Wu, Bin
• Format: Article
• Language: English
• Subjects: Aerobic glycolysis; Animals; Carcinogenesis - genetics; Carcinoma, Hepatocellular - pathology; Cell growth; Gene expression; Genomes; Glucose; Glycolysis; Hemangioma; Hepatitis B; Hepatitis B virus X protein; Hepatocellular carcinoma; Hexokinase - metabolism; Hexokinase 2; Kinases; Laboratories; Liver cancer; Liver Neoplasms - pathology; Metabolism; Metabolites; Mice; NF-kappa B - metabolism; NF-κBp65; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Survival analysis; Transgenic animals; Ultrasonic imaging
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-022-02531-x

Aerobic glycolysis has been recognized as one of the growth-promoting metabolic alterations of cancer cells. Emerging evidence indicates that nuclear factor κB (NF-κB) plays significant roles in metabolic adaptation in normal cells and cancer cells. However, whether and how NF-κB regulates metabolic reprogramming in hepatocellular carcinoma (HCC), specifically hepatitis B virus X protein (HBx)-initiated HCC, has not been determined. A dataset of the HCC cohort from the TCGA database was used to analyse the expression of NF-κB family members. Expression of NF-κBp65 and phosphorylation of NF-κBp65 (p-p65) were detected in liver tissues from HBV-related HCC patients and normal controls. A newly established HBx /NF-κBp65 and HBx /NF-κBp65 spontaneous HCC mouse model was used to investigate the effects of NF-κBp65 on HBx-initiated hepatocarcinogenesis. Whether and how NF-κBp65 is involved in aerobic glycolysis induced by HBx in hepatocellular carcinogenesis were analysed in vitro and in vivo. NF-κBp65 was upregulated in HBV-related HCC, and HBx induced NF-κBp65 upregulation and phosphorylation in vivo and in vitro. Hepatocyte-specific NF-κBp65 deficiency remarkably decreased HBx-initiated spontaneous HCC incidence in HBx-TG mice. Mechanistically, HBx induced aerobic glycolysis by activating NF-κBp65/hexokinase 2 (HK2) signalling in spontaneous hepatocarcinogenesis, and overproduced lactate significantly promoted HCC cell pernicious proliferation via the PI3K (phosphatidylinositide 3-kinase)/Akt pathway in hepatocarcinogenesis. The data elucidate that NF-κBp65 plays a pivotal role in HBx-initiated spontaneous HCC, which depends on hyperactive NF-κBp65/HK2-mediated aerobic glycolysis to activate PI3K/Akt signalling. Thus, phosphorylation of NF-κBp65 will be a potential therapeutic target for HBV-related HCC.