title: Decreased expression of neurofibromin contributes to epithelial-mesenchymal transition in neurofibromatosis type 1.
abstract: Plexiform and/or dermal neurofibromas are nerve sheath tumors of the peripheral nervous system that are usually present in individuals with neurofibromatosis type 1 (NF1). Neurofibromas arise from Schwann cells with biallelic inactivation of NF1, the gene that encodes neurofibromin. This protein is responsible for regulation of the Ras-mediated pathway, which has been shown to play a crucial role in epithelial-to-mesenchymal transition (EMT). EMT is a biological process that occurs during embryogenesis and wound healing and is involved in pathological processes such as organ fibrosis and cancer metastasis. However, the relationship between neurofibromin and EMT has not been elucidated. We investigated whether the EMT-related signaling pathway was upregulated in NF1-associated neurofibromas and Schwann cells by assessing the expression levels of the EMT-related transcription factors Snail, Slug, Twist, ZEB1 and ZEB2. Immunohistochemical studies and quantitative reverse transcription polymerase chain reaction revealed an increase in the expression levels of EMT-related transcription factors in neurofibroma specimens and NF1-derived Schwann cells (sNF96.2). In addition, the silencing of NF1 by siRNA induced the expression of EMT-related transcription factors in normal human Schwann cells and in epithelial-like breast cancer cells. Our findings suggest that the loss of neurofibromin activated the EMT-related signaling pathway and that the excessive mesenchymal reaction may play a key role in the development of NF1-associated neurofibromas.
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Arima
authors.forename: Hidemi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Kanako
authors.initials: K
authors.lastname: Kamata
authors.forename: Takaaki M
authors.initials: TM
authors.lastname: Goto
authors.forename: Mikako
authors.initials: M
authors.lastname: Sasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Kuramochi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D018317:Nerve Sheath Neoplasms / Q000378:metabolism / Q000473:pathology; D009455:Neurofibroma / Q000378:metabolism / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000378:metabolism* / Q000473:pathology*; D025542:Neurofibromin 1 / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D025542:Neurofibromin 1; D014157:Transcription Factors