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

Abstract

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.

• Authors: Masanori Matsui, Sanae Machida, Teru Itani-Yohda, Toshitaka Akatsuka
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 17 Issue 8 Pg. 897-907 (Aug 2002) ISSN: 0815-9319 [Print] Australia
• PMID: 12164966 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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