Complicated mechanisms of class II transactivator transcription deficiency in small cell lung cancer and neuroblastoma.
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.
Yazawa
Takuya
T
Department of Pathology, Yokohama City University School of Medicine, Kanagawa, Japan. tkyazawa@med.yokohama-cu.ac.jp
Ito
Takaaki
T
Kamma
Hiroshi
H
Suzuki
Takehisa
T
Okudela
Koji
K
Hayashi
Hiroyuki
H
Horiguchi
Hisashi
H
Ogata
Takesaburo
T
Mitsui
Hideaki
H
Ikeda
Masaichi
M
Kitamura
Hitoshi
H
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
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