NF1 gene silencing induces upregulation of vascular endothelial growth factor expression in both Schwann and non-Schwann cells

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-1 alpha - 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-1 alpha 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-1 alpha - VEGF pathway. We also showed that interleukin-6 is upregulated in Nf1 gene knock-down Schwann cells at the protein level.