Downregulation of the proteasome subunits, transporter, and antigen presentation in hepatocellular carcinoma, and their restoration by interferon-gamma

J Gastroenterol Hepatol. 2002 Aug;17(8):897-907. doi: 10.1046/j.1440-1746.2002.02837.x.


Background: In our previous study, expressions of human histocompatibility leukocyte antigens class I molecules (HLA-I) and the transporter associated with antigen processing (TAP) 1/2 genes were investigated in seven hepatocellular carcinoma (HCC) cell lines. Two cell lines, Hep-3B and HuH-7, showed a reduced level of TAP, which might cause the low surface expression of HLA-I. In order to understand the downregulation mechanism of antigen presentation in tumors, the two cell lines were further investigated.

Methods: Expressions of HLA-I and antigen presentation-related genes were analyzed by flow cytometry and polymerase chain reaction, respectively. Antigen presentation was tested in 51Cr-release assays.

Results: Flow cytometric analyses revealed low surface expression of HLA-I on Hep-3B and HuH-7 cells. Introduction of HLA-A2 gene did not result in a high surface expression of HLA-A2. This suggested the downregulation of HLA-I expression might be related to defects in the antigen presentation machinery. We then examined expression levels of various antigen presentation-related genes. Hep-3B and HuH-7 demonstrated low expression of the low-molecular-weight protein (LMP) 2, LMP7, TAP1, and HLA-I heavy-chain transcripts. The downregulation of these genes was dissolved by treatment with gamma-interferon. Furthermore, allo-specific cytotoxic T lymphocyte (CTL) lines failed to recognize Hep-3B and HuH-7 cells, while they killed IFN-gamma-treated Hep-3B and HuH-7 cells.

Conclusions: Our results suggest that defects in the antigen presentation-related molecules might cause downregulation of HLA-I expression, antigen presentation, and subsequently, escape from specific CTL killing. The downregulation could be restored by IFN-gamma treatment, suggesting the potential use of IFN-gamma for therapeutic purposes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation / genetics
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / genetics*
  • Cysteine Endopeptidases / genetics*
  • Down-Regulation / genetics*
  • HLA-A2 Antigen / genetics*
  • Histocompatibility Antigens Class I / genetics*
  • Humans
  • In Vitro Techniques
  • Interferon-gamma / genetics*
  • Interferon-gamma / therapeutic use
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / genetics*
  • Membrane Transport Proteins / genetics*
  • Multienzyme Complexes / genetics*
  • Proteasome Endopeptidase Complex
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • HLA-A2 Antigen
  • Histocompatibility Antigens Class I
  • Membrane Transport Proteins
  • Multienzyme Complexes
  • Interferon-gamma
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex