title: Complicated mechanisms of class II transactivator transcription deficiency in small cell lung cancer and neuroblastoma.
abstract: Small cell lung cancer (SCLC) and neuroblastoma (NB), the most aggressive adult and infant neuroendocrine cancers, respectively, are immunologically characterized by a severe reduction in major histocompatibility complex (MHC) that is indispensable for anti-tumor immunity. We had reported that the severe reduction of MHC in SCLC was caused by a deficient interferon (IFN)-gamma-inducible expression of class II transactivator (CIITA) that is known as a very important transcription factor for IFN-gamma-inducible class II and class I MHC expression (Yazawa T, Kamma H, Fujiwara M, Matsui M, Horiguchi H, Satoh H, Fujimoto M, Yokohama K, Ogata T: Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer. J Pathol 1999, 187:191-199). Here, we demonstrate that the reduction of MHC in NB was also caused by a deficient IFN-gamma-inducible expression of CIITA and that the deficiency in SCLC and NB was caused by similar mechanisms. Human achaete-scute complex homologue (HASH)-1, L-myc, and N-myc, which are specifically overexpressed in SCLC and NB, bound to the E-box in CIITA promoter IV and reduced the transcriptional activity. Anti-sense oligonucleotide experiments revealed that overexpressed L-myc and N-myc lie upstream in the regulatory pathway of HASH-1 expression. The expression of HASH-1 was also up-regulated by IFN-gamma. Our results suggest that SCLC and NB have complicated mechanisms of IFN-gamma-inducible CIITA transcription deficiency through the overexpressed HASH-1, L-myc, and N-myc. These complicated mechanisms may play an important role in the escape from anti-tumor immunity.
authors.affiliation: Department of Pathology, Yokohama City University School of Medicine, Kanagawa, Japan. tkyazawa@med.yokohama-cu.ac.jp
authors.forename: Takuya
authors.initials: T
authors.lastname: Yazawa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kamma
authors.forename: Takehisa
authors.initials: T
authors.lastname: Suzuki
authors.forename: Koji
authors.initials: K
authors.lastname: Okudela
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Horiguchi
authors.forename: Takesaburo
authors.initials: T
authors.lastname: Ogata
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mitsui
authors.forename: Masaichi
authors.initials: M
authors.lastname: Ikeda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kitamura
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000276:immunology; D009447:Neuroblastoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D014157:Transcription Factors; C065500:ASCL1 protein, human; C083728:MHC class II transactivator protein