Coexpression of major histocompatibility complex class II with chemokines and nuclear NFkappaB p50 in melanoma: a rational for their association with poor prognosis.
The constitutive expression of major histocompatibility complex class II (MHC II) molecules in melanoma is highly unusual and has been associated with unfavorable clinical outcome and higher metastatic dissemination. This association remains poorly understood and therefore, in this study we looked to whether it is caused by intracellular events that promote tumor progression. We previously reported that MHC II expression in melanoma cells requires active mitogen-activated protein kinase/extracellular signal-related kinase. However, our comparative and molecular analyses of a panel of melanoma cell lines herein provide clear evidence that mitogen-activated protein kinase/extracellular signal-related kinase is not sufficient for HLA-DR expression. We found that the expression of HLA-DR in these tumors rather coincides with the expression of CXCL-1 and CXCL-8 chemokines, both known to be expressed in tumors that invade early and are related to invasive stages of melanoma. The expression of HLA-DR also nicely paralleled that of the nuclear NFkappaB p50 subunit, regulating the expression of these chemokines in melanoma and previously correlated with poor prognosis of melanoma patients, although we provide evidence that NFkappaB is not directly regulating MHC II expression level. The molecular basis for class II transactivator and HLA-DR expression in melanoma therefore remains unsolved, but our findings linking together the expression of HLA-DR, of chemokines involved in invasiveness, and of nuclear NFkappaB p50 strongly support the content that MHC II may be a marker of invasive primary melanoma, and could explain the long-standing association of MHC II expression with overall poor prognosis and unfavorable clinical outcome.
Martins
Isabelle
I
Regulation des Reponses Immunitaires, CNRS, Institut Jacques Monod, INSERM, Reponses Immunes: Regulation et Développement, Institut Universitaire d'Hematologie, Paris, France.
Sylla
Khaoussou
K
Deshayes
Frederique
F
Lauriol
Jessica
J
Ghislin
Stephanie
S
Dieu-Nosjean
Marie-Caroline
MC
Viguier
Manuelle
M
Verola
Olivier
O
Charron
Dominique
D
Alcaide-Loridan
Catherine
C
Al-Daccak
Reem
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D045744:Cell Line, Tumor; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D018925:Chemokines; D006684:HLA-DR Antigens; C083728:MHC class II transactivator protein; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009687:Nuclear Proteins; D015534:Trans-Activators; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020781:Matrix Metalloproteinase 1