What is the role of the HBxAg (antigen for the X gene of HBV) in the hepatocarcinogenic activity of hepatitis B (HBV) (Hep B) infection?

Updated: Jun 08, 2021
  • Author: Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF; Chief Editor: BS Anand, MD  more...
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Most likely, the HBxAg produced by these sequences is the transactivating factor, because it has been found to bind to a variety of transcription factors such as CREB (cyclic adenosine monophosphate [cAMP]–response element-binding protein) and ATF-2 (activating transcription factor 2), which alters their DNA-binding specificity. Thus, the ability of the HBV pX protein to interact with cellular factors broadens the DNA-binding specificity of these regulatory proteins and provides a mechanism for pX to participate in transcriptional regulation. This shifts the pattern of host gene expression relevant to the development of HCC.

Additionally, HBxAg has been postulated to bind to the C-terminus and inactivate the product of the tumor suppressor gene TP53, as well as to do the following:

  • Sequester TP53 in the cytoplasm, resulting in the abrogation of TP53 -induced apoptosis (although controversy exists regarding this concept)

  • Reduce the ability for nucleotide excision repair by directly acting with proteins associated with DNA transcription and repair such as XPB and XPD

  • Reduce p21WAF1 expression, which is a cell cycle regulator

  • Bind to protein p55sen, which is involved in the cell fate during embryogenesis and is found in the liver of patients with hepatitis B, thus altering its function

The levels of tumor necrosis factor-alpha (TNF-a), a proinflammatory cytokine, are also upregulated. The transcriptional transactivation of nitric oxide (NO) synthetase II by pX and the elevated levels of TNF-a are responsible for the high levels of NO found in these patients. NO is a putative mutagen through several mechanisms of functional modifications of TP53, DNA oxidation, deamination, and formation of the carcinogenic N-nitroso compounds. A second transactivator is encoded in the pre-S/S region of the HBV genome, stimulating the expression of the human proto-oncogenes c-fos and c-myc; this upregulates the expression of TGF-a by transactivation.

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