ISPO

Constitutive expression of MHC class II molecules in melanoma cell lines is due to a constitutive transcription of CIITA from its promoter III

V Deffrennes1, J Vedrenne, PhD1, MC Stolzenberg, PhD1, G Barbieri, PhD1, F Baton1, J Piskurich, PhD2, J Ting, PhD2, D Charron, MD & PhD1 and C Alcaide-Loridan, PhD1

1 INSERM U396, Centre de Recherches Biomedicales des Cordeliers, Paris, France; 2 Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, Chapel Hill, NC, USA.

Constitutive expression of MHC II (Major Histocompatibility class II) molecules in melanoma tumors has been associated with a poor prognosis. Cell-surface MHC II expression was analyzed in 20 different human melanoma cell lines. Two main different patterns of MHC II expression were observed, either an interferon gamma (IFNg) inducible expression, resembling that described for melanocytes, or a constitutive expression, i.e. IFNg-independent. The hypothesis of a general abnormality of the IFNg transduction pathway was first dismissed. The class II Transactivator (CIITA) creates the proper scaffold of the transcriptional complex associated with the MHC II gene promoters, and drives the tissue-specific expression of MHC II. In agreement with these data, we have observed the constitutive expression of CIITA transcripts in melanoma cell lines expressing MHC II constitutively. Unexpectedly, these transcripts initiate from the lymphocyte-specific promoter of the CIITA gene. The constitutive expression of CIITA was next demonstrated to be linked to the presence of the enhancer located upstream of this promoter, which was previously described in epitheloid cells as an IFNg-response sequence. Luciferase assays further assessed the existence of a factor acting in trans on the enhancer in three unrelated melanoma cell lines. We therefore propose that MHC II dysregulation in melanoma is not a random event but more likely linked to the neoplastic state of these tumor cells. We have additionally demonstrated that CIITA expression from its lymphocytic promoter generates a specific isoform. We therefore propose that this CIITA isoform might display specific activities linked with the tumor growth or progression.

KEY WORDS: melanoma, MHC class II, transcription regulation.

For more information, contact Catherine.Alcaide@bhdc.jussieu.fr

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prognostic Markers.

http://www.cancerprev.org/Journal/Issues/26/101/1294/4480