[P2-164] Decreased IFITM1 expression is closely associated with tumor progression of plexiform neurofibromas in Neurofibromatosis type 1
Neurofibromatosis type 1 (NF1) is one of the most commonly inherited autosomal dominant human genetic disorder with an incidence of approximately 1 in 3000~3500 individuals worldwide. NF1 is caused by loss-of-function mutations in the NF1 gene encoding neurofibromin, a GTPase-activating protein. Since bi-allelic inactivation of NF1 gene is not sufficient to explain the pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) to malignant peripheral nerve sheath tumors (MPNSTs), other genetic changes have been suggested to be involved in MPNST pathogenesis. Here we found that interferon-induced transmembrane protein 1 (IFITM1) protein was down-regulated in NF1-deficient MPNST tissues compared to that in NF1-deficient PN tissues by immunohistochemical staining and primary-cultured MPNST cells by Western blot analysis. Overexpression of IFITM1 in NF1-deficient MPNST tumor cells resulted in a decrease in RAS activation (GTP-RAS) and its downstream ERK1/2 activation (phosphorylated ERK1/2), while downregulation of IFITM1 by treatment of small interfering RNA in normal-phenotypic NF1-deficient cells caused an increase in RAS and ERK1/2 activation, indicating that expression level of IFITM1 is closely associated with tumor progression of PNs in NF1. Treatment of interferon-alpha in the MPNST cells caused elevated expression of IFITM1, thereby leading to a decrease in the RAS activation. Our results may provide a new potential target for chemotherapy in the NF1 patients with MPNSTs. [This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (HI14C2296)].