C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism

Oncogene. 2021 Feb;40(6):1147-1161. doi: 10.1038/s41388-020-01593-5. Epub 2020 Dec 15.


Chronic hepatitis B virus (HBV) infection is strongly associated with the initiation and development of hepatocellular carcinoma (HCC). However, the genetic alterations and pathogenesis mechanisms remain significantly unexplored, especially for HBV-induced metabolic reprogramming. Analysis of integration breakpoints in HBV-positive HCC samples revealed the preferential clustering pattern within the 3'-end of X gene in the HBV genome, leading to the production of C-terminal truncated X protein (Ct-HBx). In this study, we not only characterized the oncogenic role of two Ct-HBx (HBx-120 and HBx-134) via in vitro and in vivo functional assays but also deciphered their underlying molecular mechanisms. Gene expression profiling by transcriptome sequencing identified potential targets of Ct-HBx and novel malignant hallmarks such as glycolysis, cell cycle, and m-TORC1 signaling in Ct-HBx-expressing cells. TXNIP, a well-established regulator of glucose metabolism, was shown to be downregulated by Ct-HBx and play a pivotal role in Ct-HBx-mediated HCC progression. Suppression of TXNIP is frequently observed in HCC patients with Ct-HBx expression and significantly (P = 0.015) correlated to a poorer prognosis. Re-introduction of TXNIP attenuated the metabolic reprogramming induced by the Ct-HBx and inhibited the tumor growth in the mice model. Further study suggested that Ct-HBx could downregulate TXNIP via a transcriptional repressor nuclear factor of activated T cells 2 (NFACT2). Collectively, our findings indicate that TXNIP plays a critical role in Ct-HBx-mediated hepatocarcinogenesis, serving as a novel therapeutic strategy in HCC treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Carcinogenesis / genetics
  • Carcinoma, Hepatocellular / complications
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / virology
  • Carrier Proteins / genetics*
  • Cell Line, Tumor
  • Cellular Reprogramming / genetics
  • Glycolysis / genetics
  • Hepatitis B virus / genetics
  • Hepatitis B virus / metabolism
  • Hepatitis B virus / pathogenicity
  • Hepatitis B, Chronic / complications
  • Hepatitis B, Chronic / genetics
  • Hepatitis B, Chronic / metabolism
  • Hepatitis B, Chronic / virology
  • Humans
  • Liver Neoplasms / complications
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / virology
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • NFATC Transcription Factors / genetics*
  • Trans-Activators / genetics*
  • Transcriptome
  • Viral Regulatory and Accessory Proteins / genetics*


  • Carrier Proteins
  • NFATC Transcription Factors
  • TXNIP protein, human
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • hepatitis B virus X protein
  • Mechanistic Target of Rapamycin Complex 1