Increase in HLA-G1 proteolytic shedding by tumor cells: a regulatory pathway controlled by NF-kappaB inducers.
HLA-G is expressed by tumors, in which it contributes to the evasion of immunosurveillance. NF-kappaB appears to be a candidate for regulating HLA-G expression, since it is considered to be a hallmark of cancer. We investigated the role of NF-kappaB in modulating HLA-G expression in HLA-G-positive tumor cells, JEG-3 (choriocarcinoma), FON (melanoma), and M8-HLA-G1 (HLAG1-transfected melanoma). The treatment of tumor cells with two NF-kappaB inducers, tumor necrosis factor-alpha and phorbol 12-myristate 13-acetate, decreased HLA-G1 cell surface expression but increased intracytoplasmic HLA-G proteins. Reduction in HLA-G1 cell surface expression is driven by NF-kappaB and involves a proteolytic shedding process dependent on metalloproteinase activity. In contrast, an increase in intracytoplasmic HLA-G proteins involves post-transcriptional mechanisms that are independent of NF-kappaB. These results, and the fact that soluble HLA-G1 reduces the cytotoxicity of the NKL cell line, lead us to propose a novel regulatory pathway for HLA-G expression by tumor cells that may have particular relevance in tumor escape.
Zidi
I
I
CEA, Service de Recherches en Hémato-Immunologie, DSV/DRM, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, 1 avenue Claude-Vellefaux, 75010 Paris, France.
Guillard
C
C
Marcou
C
C
Krawice-Radanne
I
I
Sangrouber
D
D
Rouas-Freiss
N
N
Carosella
E D
ED
Moreau
P
P
D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology; D002822:Choriocarcinoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D015972:Gene Expression Regulation, Neoplastic; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007157:Immunologic Surveillance; D007694:Killer Cells, Natural / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D046188:Protein Modification, Translational / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D019139:Tumor Escape; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate