Different levels of control prevent interferon-γ-inducible HLA-class II expression in human neuroblastoma cells

Michela Croce, Alessandro De Ambrosis, Maria V. Corrias, Vito Pistoia, Marzia Occhino, Raffaella Meazza, Julien Giron-Michel, Bruno Azzarone, Roberto S. Accolla, Silvano Ferrini

Research output: Contribution to journalArticle

Abstract

The HLA class II expression is controlled by the transcriptional activator CIITA. The transcription of CIITA is controlled by different promoters, among which promoter-IV is inducible by IFN-γ. We analysed the regulation of HLA class II molecules by IFN-γ in a large series of human neuroblastoma cell lines. No induction of surface or intracellular HLA class II molecules and of specific mRNA was observed, in all neuroblastomas, with the exception of a nonprototypic cell line, ACN. In a large subset of neuroblastomas IFN-γ induced expression of CIITA mRNA, derived from promoter-IV, which was not methylated. In contrast, in another subset of neuroblastomas, CIITA was not inducible by IFN-γ and CIITA promoter-IV was either completely or partially methylated. Interestingly, the use of DNA demethylating agents restored CIITA gene transcriptional activation by IFN-γ, but not HLA class II expression. The defect of HLA class II was not related to alterations in RFX or NF-Y transcription factors, as suggested by EMSA or RFX gene transfection experiments. In addition, the transfection of a functional CIITA cDNA failed to induce HLA class II expression in typical neuroblastoma cells. Confocal microscopy and Western blot analysis suggested a defective nuclear translocation and/or reduced protein synthesis in CIITA-transfected NB cells. Altogether, these data point to multiple mechanisms preventing HLA class II expression in the neuroblastoma, either involving CIITA promoter-IV silencing, or acting at the CIITA post-transcriptional level.

Original languageEnglish
Pages (from-to)7848-7857
Number of pages10
JournalOncogene
Volume22
Issue number49
DOIs
Publication statusPublished - Oct 30 2003

Keywords

  • CIITA
  • HLA class II
  • Neuroblastoma
  • Promoter methylation

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

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  • Cite this

    Croce, M., De Ambrosis, A., Corrias, M. V., Pistoia, V., Occhino, M., Meazza, R., Giron-Michel, J., Azzarone, B., Accolla, R. S., & Ferrini, S. (2003). Different levels of control prevent interferon-γ-inducible HLA-class II expression in human neuroblastoma cells. Oncogene, 22(49), 7848-7857. https://doi.org/10.1038/sj.onc.1207054