2. Academic Validation
  3. Aerobic glycolysis enhances HBx-initiated hepatocellular carcinogenesis via NF-κBp65/HK2 signalling

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

  • J Exp Clin Cancer Res. 2022 Nov 21;41(1):329. doi: 10.1186/s13046-022-02531-x.
Lingjun Chen # 1 2,  Xianyi Lin # 1 2,  Yiming Lei 1 2,  Xuan Xu 1 2,  Qi Zhou 1 2,  Yan Chen 1 2,  Huiling Liu 1 2,  Jie Jiang 1 2,  Yidong Yang 1 2,  Fengping Zheng 1 2,  Bin Wu 3 4
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong Province, China.
  • 2 Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, Guangdong Province, China.
  • 3 Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong Province, China. wubin6@mail.sysu.edu.cn.
  • 4 Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, Guangdong Province, China. wubin6@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 36411480 DOI: 10.1186/s13046-022-02531-x
Abstract

Background: 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.

Methods: 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-κBp65f/f and HBx+/+/NF-κBp65Δhepa 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.

Results: 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.

Conclusion: 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.

Keywords

Aerobic glycolysis; Hepatitis B virus X protein; Hepatocellular carcinoma; Hexokinase 2; NF-κBp65.

Figures
Products