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Distinct mechanisms of loss of IFN-gamma mediated HLA class I inducibility in two melanoma cell lines.

AbstractBACKGROUND:
The inability of cancer cells to present antigen on the cell surface via MHC class I molecules is one of the mechanisms by which tumor cells evade anti-tumor immunity. Alterations of Jak-STAT components of interferon (IFN)-mediated signaling can contribute to the mechanism of cell resistance to IFN, leading to lack of MHC class I inducibility. Hence, the identification of IFN-gamma-resistant tumors may have prognostic and/or therapeutic relevance. In the present study, we investigated a mechanism of MHC class I inducibility in response to IFN-gamma treatment in human melanoma cell lines.
METHODS:
Basal and IFN-induced expression of HLA class I antigens was analyzed by means of indirect immunofluorescence flow cytometry, Western Blot, RT-PCR, and quantitative real-time RT-PCR (TaqMan(R) Gene Expression Assays). In demethylation studies cells were cultured with 5-aza-2'-deoxycytidine. Electrophoretic Mobility Shift Assay (EMSA) was used to assay whether IRF-1 promoter binding activity is induced in IFN-gamma-treated cells.
RESULTS:
Altered IFN-gamma mediated HLA-class I induction was observed in two melanoma cells lines (ESTDAB-004 and ESTDAB-159) out of 57 studied, while treatment of these two cell lines with IFN-alpha led to normal induction of HLA class I antigen expression. Examination of STAT-1 in ESTDAB-004 after IFN-gamma treatment demonstrated that the STAT-1 protein was expressed but not phosphorylated. Interestingly, IFN-alpha treatment induced normal STAT-1 phosphorylation and HLA class I expression. In contrast, the absence of response to IFN-gamma in ESTDAB-159 was found to be associated with alterations in downstream components of the IFN-gamma signaling pathway.
CONCLUSION:
We observed two distinct mechanisms of loss of IFN-gamma inducibility of HLA class I antigens in two melanoma cell lines. Our findings suggest that loss of HLA class I induction in ESTDAB-004 cells results from a defect in the earliest steps of the IFN-gamma signaling pathway due to absence of STAT-1 tyrosine-phosphorylation, while absence of IFN-gamma-mediated HLA class I expression in ESTDAB-159 cells is due to epigenetic blocking of IFN-regulatory factor 1 (IRF-1) transactivation.
AuthorsTeresa Rodríguez, Rosa Méndez, Ana Del Campo, Pilar Jiménez, Natalia Aptsiauri, Federico Garrido, Francisco Ruiz-Cabello
JournalBMC cancer (BMC Cancer) Vol. 7 Pg. 34 (Feb 23 2007) ISSN: 1471-2407 [Electronic] England
PMID17319941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • HLA Antigens
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Interferon-gamma
Topics
  • Antineoplastic Agents (pharmacology)
  • Epigenesis, Genetic
  • Genes, MHC Class I
  • HLA Antigens (biosynthesis)
  • Humans
  • Interferon Regulatory Factor-1 (metabolism)
  • Interferon-gamma (pharmacology)
  • Melanoma (immunology, metabolism)
  • Phosphorylation
  • STAT1 Transcription Factor (metabolism)
  • Signal Transduction
  • Skin Neoplasms (immunology, metabolism)
  • Transcriptional Activation
  • Tumor Cells, Cultured

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