title: Uterine Leiomyosarcoma Tumorigenesis in Lmp2-deficient Mice: Involvement of Impaired Anti-oncogenic Factor IRF1.
abstract: OBJECTIVE
  Uterine leiomyosarcoma (Ut-LMS) is a highly metastatic smooth muscle neoplasm. We have previously reported that low molecular mass protein2 Lmp2-deficient mice spontaneously developed Ut-LMS, which implicated this protein as an anti-oncogenic candidate. We also suggested that LMP2 may negatively regulate Ut-LMS independently of its role in the proteasome. Initially described as a transcription factor able to activate the expression of interferon-gamma (IFN-γ)-responsive genes, interferon regulatory factor-1 (IRF1) has been shown to play roles in the immune response, and tumor suppression. The aim of this study was to elucidate the molecular mechanism of sarcomagenesis of Ut-LMS using human and mouse uterine tissues.
  
  
  METHODS
  The expression of the IFN-γ signal molecules, IRF1 and -2, STAT1, and LMP2, -3, -7 and -10 were examined by western blot analysis, electrophoretic mobility shift assay and immunohistochemistry in human and mouse uterine tissues. Physiological significance of IRF1 in sarcomagenesis of Ut-LMS was demonstrated by xenograft studies.
  
  
  RESULTS
  In the present study, several lines of evidence indicated that although treatment with IFN-γ strongly induced the activation of STAT1 as a transcriptional activator, its target molecule, IRF1, was not clearly produced in Lmp2-deficient uterine smooth muscle cells (Ut-SMCs).
  
  
  CONCLUSIONS
  Defective expression of IRF1 in the IFN-γ-induced signaling molecules may result in the malignant transformation of Ut-SMCs. The modulation of LMP2 may lead to new therapeutic approaches in human Ut-LMS.
authors.affiliation: Department of Immunology and Infectious Disease, Shinshu University Graduate School of Medicine, Asahi, Matsumoto, Nagano, Japan Promoting Business using Advanced Technology, Japan Science and Technology Agency (JST), Chiyoda, Tokyo, Japan yoyoyo224@hotmail.com.
authors.forename: Takuma
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Horiuchi Ladies Clinic, Matsumoto, Nagano, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Horiuchi
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Nagano, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sano
authors.affiliation: Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yaegashi
authors.affiliation: Department of Obstetrics and Gynecology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D003546:Cysteine Endopeptidases / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D007371:Interferon-gamma; D007890:Leiomyosarcoma / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014594:Uterine Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000951:Antigens, Neoplasm; D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; D016159:Tumor Suppressor Protein p53; C071313:LMP-2 protein; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases
keywords: IFN-γ; IRF1; LMP2; smooth muscle cell; uterine leiomyosarcoma