Hepatitis B virus X protein promotes tumor glycolysis by downregulating lncRNA OIP5-AS1/HKDC1 in HCC

Cell Signal. 2024 Jul:119:111183. doi: 10.1016/j.cellsig.2024.111183. Epub 2024 Apr 16.

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, with Hepatitis B virus (HBV) infection being the leading cause. This study aims to investigate the role of HBV in HCC pathogenesis involving glucose metabolism. Long non-coding RNA (lncRNA) OIP5-AS1 was significantly downregulated in HBV-positive HCC patients, and its low expression indicated a poor prognosis. This lncRNA was primarily localized in the cytoplasm, acting as a tumor suppressor. HBV protein X (HBx) repressed OIP5-AS1 expression by inhibiting a ligand-activated transcriptional factor peroxisome proliferator-activated receptor α (PPARα). Furthermore, mechanistic studies revealed that OIP5-AS1 inhibited tumor growth by suppressing Hexokinase domain component 1 (HKDC1)-mediated glycolysis. The expression of HKDC1 could be enhanced by transcriptional factor sterol regulatory element-binding protein 1 (SREBP1). OIP5-AS1 facilitated the ubiquitination and degradation of SREBP1 to suppress HKDC1 transcription, which inhibited glycolysis. The results suggest that lncRNA OIP5-AS1 plays an anti-oncogenic role in HBV-positive HCC via the HBx/OIP5-AS1/HKDC1 axis, providing a promising diagnostic marker and therapeutic target for HBV-positive HCC patients.

Keywords: Glycolysis; HBx; HCC; HKDC1; LncRNA-OIP5-AS1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Carcinoma, Hepatocellular* / virology
  • Cell Line, Tumor
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Glycolysis* / genetics
  • Hepatitis B virus
  • Hexokinase* / genetics
  • Hexokinase* / metabolism
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Liver Neoplasms* / virology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Trans-Activators* / genetics
  • Trans-Activators* / metabolism
  • Viral Regulatory and Accessory Proteins*

Substances

  • RNA, Long Noncoding
  • hepatitis B virus X protein
  • Viral Regulatory and Accessory Proteins
  • long noncoding RNA OIP5, human
  • Trans-Activators
  • Hexokinase
  • Sterol Regulatory Element Binding Protein 1
  • PPAR alpha