title: NF1 gene silencing induces upregulation of vascular endothelial growth factor expression in both Schwann and non-Schwann cells.
abstract: Neurofibromatosis type I (NF1) is associated with typical hypervascular tumors, including neurofibroma, glioma, malignant peripheral nerve sheath tumors (MPNST) and glomus tumors. Previously, we and other groups reported that neurofibromas showed high-level expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor involved in neovascularization. However, the molecular mechanism underlying the upregulation of VEGF in neurofibromas remains unclear. In this study, we examined the effects of Nf1 gene silencing on VEGF expression in Schwann cell and non-Schwann cell line and the upstream mTOR-HIF-1α - VEGF pathway in Schwann cell line. The results indicated that Nf1 gene silencing by lentiviral-mediated RNA interference resulted in elevated expression of VEGF, HIF-1α and phosphorylated mTOR at the protein level. The results obtained from Nf1 gene silencing in murine Schwann cell line analogously suggest that NF1 gene haploinsufficiency in human tumor Schwann cells may directly elicit upregulation of VEGF expression without the tumor microenvironment by activation of the mTOR-HIF-1α - VEGF pathway. We also showed that interleukin-6 is upregulated in Nf1 gene knock-down Schwann cells at the protein level.
authors.affiliation: Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Japan. kyasuhir@md.tsukuba.ac.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kawachi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maruyama
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ishitsuka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujisawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Furuta
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Eiko
authors.initials: E
authors.lastname: Ichikawa
authors.forename: Minao
authors.initials: M
authors.lastname: Furumura
authors.forename: Fujio
authors.initials: F
authors.lastname: Otsuka
mesh_terms: D000818:Animals; D002460:Cell Line; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012583:Schwann Cells / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059016:Tumor Microenvironment; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases