Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Japan.
Exp Dermatol. 2013 Apr;22(4):262-5. doi: 10.1111/exd.12115.
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.
神经纤维瘤病 1 型（NF1）与典型的高血管性肿瘤有关，包括神经纤维瘤、神经胶质瘤、恶性外周神经鞘肿瘤（MPNST）和血管球瘤。以前，我们和其他研究小组报道称，神经纤维瘤表现出高水平的血管内皮生长因子（VEGF）表达，VEGF 是一种参与新血管形成的有效的血管生成因子。然而，神经纤维瘤中 VEGF 上调的分子机制尚不清楚。在这项研究中，我们研究了 Nf1 基因沉默对施万细胞和非施万细胞系中 VEGF 表达以及施万细胞系中 mTOR-HIF-1α-VEGF 通路的上游的影响。结果表明，通过慢病毒介导的 RNA 干扰沉默 Nf1 基因导致 VEGF、HIF-1α 和磷酸化 mTOR 在蛋白水平上的表达升高。通过小鼠施万细胞系中的 Nf1 基因沉默获得的结果同样表明，人肿瘤施万细胞中 NF1 基因杂合不足可能通过 mTOR-HIF-1α-VEGF 通路的激活，在没有肿瘤微环境的情况下，直接引起 VEGF 表达的上调。我们还表明，白细胞介素-6 在 Nf1 基因敲低的施万细胞中在蛋白水平上上调。
