Class II transactivator (CIITA) isoform expression and activity in melanoma.
In contrast with melanocytes, melanomas display constitutive expression of HLA-DR (HLA-DR+). This abnormal expression has been associated with tumour progression and metastatic dissemination. We have previously reported that this deregulation of HLA-D genes is due to the abnormal constitutive expression of the lymphocyte-specific isoform of class II transactivator (B-CIITA), in addition to its fibroblast form (F-CIITA), which is usually expressed in major histocompatibility complex (MHC) class II-negative interferon-gamma-induced cell types, such as melanocytes. In this study, we investigated the abnormal expression of B-CIITA in a panel of melanoma cell lines displaying differential HLA-DR expression profiles, and analysed whether such a molecular event can participate in tumour progression. Our results showed that the abnormal expression of B-CIITA did not have any particular effect, in comparison with F-CIITA, on the classical activity of CIITA HLA-D gene regulation. As CIITA has also been shown to regulate genes other than HLA-D, we evaluated the modulation of those encoding cyclin D1, YARS (tyrosyl-tRNA synthetase) and TRIP1 (transforming growth factor (TGF)-beta receptor-interacting protein), proteins involved in cell cycle/apoptosis balance, angiogenesis and resistance to TGF-beta, respectively. In contrast with other cell types, neither B-CIITA nor F-CIITA was able to modulate these genes in melanoma cell lines. Thus, the activity of CIITA, whether lymphocyte-specific or fibroblast-specific, is restricted to HLA-D gene expression in these tumours. Accordingly, our data suggest that CIITA is not involved per se in tumour progression; rather, it is the MHC class II molecules themselves, through tumour antigen presentation and the induction of tumour antigen-specific CD4 lymphocyte anergy, that may participate in immune escape and melanoma progression.
Baton
Fabrice
F
INSERM U396, Centre de Recherches Biomédicales des Cordeliers, Paris, France.
Deruyffelaere
Carine
C
Chapin
Muriel
M
Prod'homme
Thomas
T
Charron
Dominique
D
Al-Daccak
Reem
R
Alcaide-Loridan
Catherine
C
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D019938:Cyclin D1 / Q000378:metabolism; D018450:Disease Progression; D039621:Eukaryotic Initiation Factor-3; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005802:Genes, MHC Class II / Q000502:physiology; D006684:HLA-DR Antigens / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000276:immunology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D011506:Proteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014448:Tyrosine-tRNA Ligase / Q000378:metabolism
D039621:Eukaryotic Initiation Factor-3; D006684:HLA-DR Antigens; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011506:Proteins; D015534:Trans-Activators; D019938:Cyclin D1; C096013:EIF3I protein, human; D014448:Tyrosine-tRNA Ligase